tripeptidyl peptidase & cholecystokinin


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(Updated 12/02)

Tomkinson B.
Characterization of cDNA for murine tripeptidyl-peptidase II reveals alternative splicing.
Biochem J 1994 Dec 1;304 ( Pt 2):517-23
"Tripeptidyl-peptidase II (TPP II) is a cytosolic high-M(r) exopeptidase with an active site of the subtilisin type. This paper describes cloning of cDNA encoding murine TPP II. Four clones were isolated from a murine mastocytoma cDNA library and the 5'-end was isolated by use of 5'-RACE (rapid amplification of cDNA ends). A total of 4611 bp were isolated, including the complete coding region. The deduced amino acid sequence shows a 96% overall identity when compared with the previously cloned human TPP II. The remarkably high identity indicates that not only the catalytic domain, but almost the entire subunit, must be of functional importance. Alignment with subtilisin-like serine peptidases identified Asp44, His264 and Ser449 as the catalytic triad, thus defining an extra domain of approximately 200 amino acids between the catalytic Asp and His in TPP II as compared with other subtilases. In addition, it was demonstrated that different polyadenylation signals can be utilized, since two different clones with untranslated 3'-ends of 155 bp and 781 bp respectively have been isolated. Finally, one of the isolated clones contains an extra 39 bp insert encoding 13 amino acids, which implies alternative splicing of the mRNA." [Abstract]

Hansen TV, Nielsen FC.
Regulation of neuronal cholecystokinin gene transcription.
Scand J Clin Lab Invest Suppl 2001;(234):61-7
"Cholecystokinin (CCK) is a neuroendocrine peptide expressed in I-cells of the small intestine and in central and peripheral neurons. Whereas intestinal CCK is involved in the release of pancreatic enzymes and the contraction of the gallbladder, cerebral CCK is implicated in a variety of functions, such as feeding behaviour, anxiety and memory. The expression of CCK is developmentally regulated. Brain CCK mRNA levels are low before birth, but increase markedly shortly after birth and reach adult like patterns of expression three weeks after birth during the final maturation of the central nervous system. In the adult, several substances induce neuronal CCK mRNA expression via activation of transcription factors binding to regulatory elements in the CCK promoter. Recent studies have examined the signaling pathways, transcription factors and regulatory elements involved in cAMP, fibroblast growth factor-2, and calcium-induced CCK gene transcription in neuronal cells. The review describes the signaling pathways and transcription factors involved in neuronal CCK gene transcription." [Abstract]

M Schalling, K Friberg, K Seroogy, P Riederer, E Bird, SN Schiffmann, P Mailleux, J Vanderhaeghen, S Kuga, M Goldstein, K Kitahama, PH Luppi, M Jouvet, and T Hokfelt
Analysis of Expression of Cholecystokinin in Dopamine Cells in the Ventral Mesencephalon of Several Species and in Humans with Schizophrenia
PNAS 87: 8427-8431, 1990.
"The ventral mesencephalons of hamster, guinea pig, cat, monkey, and several humans with and without the diagnosis of schizophrenia were analyzed with in situ hybridization and immunohistochemistry. Extensive codistribution of cholecystokinin mRNA and tyrosine hydroxylase [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC] mRNA was observed in cats and monkeys as well as in all five human subjects with the diagnosis of schizophrenia and in two out of five control brains. Double labeling revealed coexistence of the two markers in cat, monkey, and human. No cholecystokinin mRNA or cholecystokinin peptide was detected in the substantia nigra/ventral tegmental area of the hamster or guinea pig, even after acute and chronic neuroleptic treatment." [Abstract]

Voigt JP, Sohr R, Fink H.
CCK-8S facilitates 5-HT release in the rat hypothalamus.
Pharmacol Biochem Behav 1998 Jan;59(1):179-82 [Abstract]

Poeschla B, Gibbs J, Simansky KJ, Greenberg D, Smith GP.
Cholecystokinin-induced satiety depends on activation of 5-HT1C receptors.
Am J Physiol 1993 Jan;264(1 Pt 2):R62-4
"To investigate the dependence of the satiating action of cholecystokinin on serotonergic function in rats, we examined the effects of systemic pretreatment with serotonin (5-HT) antagonists of varying selectivity for 5-HT receptor subtypes on suppression of food intake induced by systemic administration of cholecystokinin octapeptide (CCK-8). Mianserin, a 5-HT1C/2-selective antagonist, significantly attenuated the satiating action of CCK-8. Ketanserin, a 5-HT2 antagonist, and three 5-HT3 antagonists, MDL-72222, ICS 205-930, and ondansetron, however, had no effect on the satiating action of CCK-8. These results demonstrate that the satiating action of exogenous CCK depends on activation of 5-HT1 (probably 5-HT1C) receptors and that activation of 5-HT2 or 5-HT3 receptors is not required." [Abstract]

Migaud M, Roques BP, Durieux C.
Evidence for a high-affinity uptake system for cholecystokinin octapeptide (CCK8) in rat cortical synaptosomes.
Eur J Neurosci 1995 May 1;7(5):1074-9
"Given the high resistance of the cholecystokinin octapeptide (CCK8) to in vivo peptidase degradation, the possible existence of a reuptake system for this peptide was investigated. Efficient accumulation of intact, tritiated propionyl CCK8 ([3H]pCCK8) was observed following its incubation with rat cortical synaptosomes but not with cerebellar synaptosomes, where no cholecystokinin immunoreactivity was found. This uptake process appeared to be dependent on temperature, duration of incubation, concentration of radioligand, the presence of glucose and the integrity of the synaptosomes. A Lineweaver-Burk analysis indicated that the putative uptake process is characterized by a single Km value of 10.7 nM and a Vmax of 8.5 fmol/min/mg of protein. Carbonyl cyanide-m-chlorophenyl hydrazone, an uncoupler of oxidative phosphorylation, blocked accumulation of [3H]pCCK8, whereas ouabain did not. The uptake was found to be highly specific since, among all the cholecystokinin analogues tested, only CCK8 and, to a lesser extent, CCK7, were able to inhibit [3H]pCCK8 uptake. The rate of [3H]pCCK8 uptake was not affected by CCK4, CCK5, D-Trp CCK8, BC 264, a potent and radioactivity was observed using [3H]pBC 264, a result which is not in favour of a cholecystokinin receptor-induced internalization mechanism. The potent and selective uptake mechanism characterized in this study could participate, in conjunction with extra and intracellular degradation of CCK8 by peptidases, in the interruption of cholecystokinin-conveyed messages in the brain." [Abstract]

Evelyn W. Wang, Benedikt M. Kessler, Anna Borodovsky, Benjamin F. Cravatt, Matthew Bogyo, Hidde L. Ploegh, and Rickard Glas
Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity
PNAS 97: 9990-9995; published online before print as 10.1073/pnas.180328897
"Cytosolic proteolysis is carried out predominantly by the proteasome. We show that a large oligopeptidase, tripeptidylpeptidase II (TPPII), can compensate for compromised proteasome activity. Overexpression of TPPII is sufficient to prevent accumulation of polyubiquitinated proteins and allows survival of EL-4 cells at otherwise lethal concentrations of the covalent proteasome inhibitor NLVS (NIP-leu-leu-leu-vinylsulfone). Elevated TPPII activity also partially restores peptide loading of MHC molecules. Purified proteasomes from adapted cells lack the chymotryptic-like activity, but still degrade longer peptide substrates via residual activity of their Z subunits. However, growth of adapted cells depends on induction of other proteolytic activities. Therefore, cytosolic oligopeptidases such as TPPII normalize rates of intracellular protein breakdown required for normal cellular function and viability." [Full Text]

Wilms K, Vierig G, Davidowa H.
Interactive effects of cholecystokinin-8S and various serotonin receptor agonists onthe firing activity of neostriatal neuronesin rats.
Neuropeptides 2001 Oct;35(5-6):257-70 [Abstract]

Voigt JP, Sohr R, Fink H.
CCK-8S facilitates 5-HT release in the rat hypothalamus.
Pharmacol Biochem Behav 1998 Jan;59(1):179-82
"The effects of the neurotransmitter serotonin (5-HT) and the neuropeptide cholecystokinin (CCK) on food intake are well established. Based on pharmacological studies, an interactive model for 5-HT and CCK was proposed. The present microdialysis study was aimed to provide neurochemical evidence for a facilitatory effect of CCK-8S on 5-HT release in the lateral hypothalamus under in vivo conditions. The results indicate an increase of extracellular hypothalamic 5-HT both during food intake in previously food-deprived rats and also after systemic administration of 8 microg/kg and 40 microg/kg CCK-8s in food-deprived rats. The results show that peripherally administered CCK-8s induces central serotonergic effects, possibly related to feeding." [Abstract]

Ladurelle N, Keller G, Blommaert A, Roques BP, Dauge V.
The CCK-B agonist, BC264, increases dopamine in the nucleus accumbens and facilitates motivation and attention after intraperitoneal injection in rats.
Eur J Neurosci 1997 Sep;9(9):1804-14
"Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK4, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (microg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D1 (SCH23390, 25 microg/kg i.p.) or D2 (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects." [Abstract]

Dauge V, Lena I.
CCK in anxiety and cognitive processes.
Neurosci Biobehav Rev 1998 Oct;22(6):815-25
"Extensive studies were carried out on the involvement of the CCKergic system in anxiety-, panic- and stress-related behaviour. The stimulation of CCK-A or CCK-B receptors is implicated in the physical and psychological responses of CCK to stress. Furthermore, several selective CCK-B agonists produce anxiogenic-like effects, while CCK-B antagonists induce anxiolytic-like responses in several models of anxiety. However, BC264 a highly selective CCK-B agonist, does not produce anxiogenic-like effects but increases attention and/or memory. These effects are dependent on the dopaminergic systems. Together with biochemical data, this led to the hypothesis of the existence of two CCK-B binding sites, CCK-B1 and CCK-B2, which could correspond to different activation states of a single molecular entity. Investigations into CCK-B1 and CCK-B2 systems might be of critical interest, since only one site, CCK-B1, appears to be responsible for the effects of anxiety. Furthermore, the improvement of attention and/or memory processes by CCK, through CCK-B2 receptors, could offer a new perspective in the treatment of attention and/or memory disorders." [Abstract]

Schreiber H, Stolz-Born G, Pietrowsky R, Kornhuber HH, Fehm HL, Born J.
Improved event-related potential signs of selective attention after the administration of the cholecystokinin analog ceruletide in healthy persons.
Biol Psychiatry 1995 May 15;37(10):702-12
"Cholecystokinin (CCK) is co-localized with dopamine (DA) in neurons of the mesolimbic-frontocortical dopamine (DA) system, considered essential for the pathology of psychotic behavior and associated attention deficits. The present experiments in 13 healthy men aimed at examining the effects of the CCK analog ceruletide on attention as reflected by event-related brain potentials (ERPs). Subjects were tested according to a double-blind cross-over design on three occasions, following intravenous infusion of placebo, 0.5 microgram ceruletide, and 2.5 micrograms ceruletide. ERPs were recorded during the subject's performance on an auditory selective attention task including the concurrent presentation of frequent standard tones and infrequent deviant tones which the subject had to listen to, or to ignore. The processing negativity (PN) over frontocentral cortical areas, reflecting selective attention, was higher after ceruletide than placebo, this increase being most pronounced after the 2.5 micrograms dose (placebo -1.29 +/- 0.38 microV versus ceruletide -3.02 +/- 0.65 microV, p < .05). ERP signs of a general increase in cortical arousal after ceruletide did not reach significance. Likewise, mismatch negativity, an indicator of preattentive processing of stimulus deviance, was not significantly affected by the peptide. The results indicate that ceruletide affects human brain function primarily by improving selective attention." [Abstract]

Tomkinson B, Zetterqvist O.
Immunological cross-reactivity between human tripeptidyl peptidase II and fibronectin.
Biochem J 1990 Apr 1;267(1):149-54
"Tripeptidyl peptidase II (TPP II) is a large intracellular exopeptidase with an active site of the subtilisin type. Affinity-purified hen antibodies against human erythrocyte TPP II cross-reacted with fibronectin in an immunoblot analysis. Furthermore, antibodies against human fibronectin cross-reacted with TPP II. Antibodies against a 65 kDa cell-binding fragment of fibronectin specifically reacted with TPP II, whereas antibodies against the collagen-binding domain, the main heparin-binding domain or the N-terminal fibrin-binding domain did not react. Moreover, the affinity-purified antibodies against TPP II reacted with a 105 kDa cell-binding fragment of fibronectin but not with the fibrin-binding domain or the collagen-binding domain. When native TPP II was dissociated into smaller units through dialysis against a dilute Tris buffer, it could be digested by chymotrypsin into three stable fragments of 70 kDa, 42 kDa and 20 kDa. It could be demonstrated that the 42 kDa fragment was specifically recognized by antibodies against the 65 kDa cell-binding fragment of fibronectin. Furthermore, labelling with di-[3H]isopropyl phosphorofluoridate and N-terminal sequence determination showed that the 70 kDa fragment contained the active-site serine residue. In conclusion, our findings suggest that one domain of the TPP II molecule bears structural resemblance to a cell-binding fragment of fibronectin."

Crawley JN.
Cholecystokinin-dopamine interactions.
Trends Pharmacol Sci 1991 Jun;12(6):232-6
"Cholecystokinin (CCK) coexists with dopamine in a large proportion of the ventral tegmental and substantia nigra neurons in rodents and primates. In this review Jacki Crawley integrates the neurophysiological, behavioral, and release studies which demonstrate both excitatory effects of CCK, and facilitatory modulating effects of CCK on the inhibitory actions of dopamine, in the mesolimbic pathway. Nonpeptide antagonists selective for the CCKA and CCKB receptors have recently been developed, and provide long-awaited tools to test hypotheses about the role of endogenous CCK as a modulator of dopaminergic function, and the potential of CCK-based drugs as treatments for neuropsychiatric disorders." [Abstract]

Becker, Chrystel, Thiebot, Marie-Helene, Touitou, Yvan, Hamon, Michel, Cesselin, Francois, Benoliel, Jean-Jacques
Enhanced Cortical Extracellular Levels of Cholecystokinin-Like Material in a Model of Anticipation of Social Defeat in the Rat
J. Neurosci. 2001 21: 262-269
"The involvement of cholecystokinin (CCK) in the mechanisms of stress and/or anxiety was assessed by in vivo microdialysis in rats subjected to a social stress paradigm. During the initial 30 min period of each conditioning session, a male Sprague Dawley rat (intruder) was placed in a protective cage inside the cage of a male Tryon Maze Dull rat (resident), allowing unrestricted visual, olfactory, and auditory contacts but precluding close physical contact between them. During the following 15 min period, both the protective cage and the resident were removed (nondefeated intruders) or only the protective cage was removed allowing the resident to attack the intruder (defeated rats). This procedure was repeated once daily for 4 d. On the fifth day, a guide cannula was implanted into the prefrontal cortex of intruders. During a single 30 min test session, performed 4 d later, intruders were subjected to only the 30 min protected confrontation to the resident. Anxiety-like behavior (immobility, ultrasonic vocalizations, and defensive postures), associated with an increase (approximately +100% above baseline) in cortical outflow of CCK-like material (CCKLM), were observed in defeated intruders. Pretreatment with diazepam (5 mg/kg, i.p.), but not buspirone (0.5-2 mg/kg, i.p.), prevented both the anxiety-related behavior and CCKLM overflow. The selective CCK-B receptor antagonist CI-988 (2 mg/kg, i.p.) reduced the anxiety-like behavior without affecting the increase in CCKLM outflow. These data indicate that anticipation of social defeat induces a marked activation of cortical CCKergic neurons associated with anxiety-related behaviors in rats." [Full Text]

Lemaire M, Bohme GA, Piot O, Roques BP, Blanchard JC.
CCK-A and CCK-B selective receptor agonists and antagonists modulate olfactory recognition in male rats.
Psychopharmacology (Berl) 1994 Aug;115(4):435-40
"Modulation of learning and memory is one of the physiological roles that the neuropeptide cholecystokinin (CCK-8) may play. We have used a behavioural model of olfactory recognition among rats to test this hypothesis and to explore the relationship between CCK-A and CCK-B receptors and memory retention. Adult male rats form a transient memory of a juvenile congenere as indicated by a reduction in the duration of investigatory behaviour upon re-exposure 30 min after an initial exposure, but not when re-exposure is delayed until 120 min afterwards. In the present study, rats were treated after the first contact with various compounds; inhibition and facilitation of olfactory recognition were evaluated as the persistence in investigation 30 min and the decrease in investigation 120 min after pharmacological manipulations, respectively. Systemic injection of CCK-8, of a selective CCK-A agonist, or of non-peptide CCK-B antagonists (CI-988 and LY-262691) enhanced olfactory recognition. In contrast, the CCK-B selective agonist BC 264 and the tetrapeptide CCK-4 both disrupted it. Taken together with previous evidence of the detrimental effect of the nonpeptide. CCK-A antagonist devazepide on olfactory recognition, these results confirm and extend the hypothesis that there is a balance between CCK-A-mediated facilitative effects and CCK-B-mediated inhibitory effects on memory retention." [Abstract]

Hansen TV, Rehfeld JF, Nielsen FC.
Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter.
Mol Psychiatry 2000 Jul;5(4):443-7
"Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Sp1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation." [Abstract]

Rich-Bennett E, Dahl D, Lecompte BB 3rd.
Modulation of paired-pulse activation in the hippocampal dentate gyrus by cholecystokinin, baclofen and bicuculline.
Neuropeptides 1993 May;24(5):263-70
"Paired-pulse stimulation was used to evaluate the effects of the sulfated octapeptide of cholecystokinin (CCK8-S), the gamma-aminobutyric acidB (GABAB) agonist (-) baclofen, and the GABAA antagonist (-) bicuculline on hippocampal dentate gyrus (DG) granule cell excitability. Evoked action potentials (EAPs) and excitatory postsynaptic potentials (EPSPs) were recorded in response to orthodromic stimulation of the medial (MPP) or lateral (LPP) perforant pathway. Paired-pulse indices were determined using interpulse intervals (IPIs) across the range of 5-1000 ms. As reported by others, three phases of paired-pulse effects were revealed under control (drug-free ACSF) conditions: early paired-pulse inhibition (PPI), intermediate paired-pulse facilitation (PPF) and late PPI. With EAPs, CCK8-S enhanced only the intermediate PPF on both pathways, with no effect on the early or late PPIs. The effects of (-) baclofen were similar to CCK8-S. (-) Bicuculline attenuated the early and late PPI as well as the PPF. No differences were measured on the MPP- or LPP-evoked EPSPs in any of the drug conditions. These results indicate a similarity of CCK8-S- with GABAB-mediated modulation on neuronal activation in the DG. CCK8-S disinhibition of DG granule cells may play a role in the induction of long-lasting synaptic modifications." [Abstract]

Wu T, Wang HL.
The excitatory effect of cholecystokinin on rat neostriatal neurons: ionic and molecular mechanisms
Eur J Pharmacol 1996 Jun 27;307(2):125-32
"Whole-cell patch-clamp recordings were performed to study ionic and molecular mechanisms by which cholecystokinin (CCK) peptides modulate the membrane excitability of acutely dissociated rat neostriatal neurons. Immunohistochemical staining studies indicated that about 95% of acutely isolated neostriatal neurons were GABA(gamma-aminobutyric acid)ergic medium-sized cells. During current-clamp recordings, sulfated cholecystokinin octapeptide (CCK-8) depolarized neostriatal neurons and evoked action potentials. During voltage-clamp recordings, CCK-8 induced inward currents at negative membrane potentials by increasing the voltage-insensitive and non-selective cationic conductance. Cholecystokinin tetrapeptide (CCK-4), a selective CCKB receptor agonist, also evoked cationic currents. The CCK-8-induced cation currents were antagonized by PD135,158 (4- inverted question mark[2-[[3-(1H-indol-3yl)-2-mehtyl-1-oxo-2-[[[1.7.7.-trimeth yl-bicyclo [2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4- oxo- [1S-1 alpha, 2 beta [S*(S*)]4 alpha] inverted question mark-butanoate N-methyl-D-glucamine), a highly specific and potent CCKB receptor antagonist. The CCK-8-evoked inward currents were blocked by the internal perfusion of 1 mM GDP-beta-S. In neostriatal neurons dialyzed with 0.5 mM GTP-gamma-S, the cationic currents produced by CCK-8 became irreversible. Pretreating neostriatal neurons with 500 ng/ml pertussis toxin did not prevent CCK-8 from evoking cationic currents. Internal administration of heparin (2 mg/ml), an inositol 1,4,5-trisphosphate (IP3) receptor antagonist, and buffering of intracellular calcium with the Ca(2+)-chelator, BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, 10 mM), suppressed CCK-8-evoked cationic currents. These findings suggest that, by activating CCKB receptors, CCK-8 excites rat neostriatal neurons through enhancing a non-selective cationic conductance and that pertussis toxin-insensitive G-proteins mediate CCK-8 enhancement of the cationic conductance. The coupling mechanism via G-proteins is likely to involve the production of IP3, and the subsequent IP3-evoked Ca2+ release leads to the opening of non-selective cation channels." [Abstract]

Stephen A. Wank
I. CCK receptors: an exemplary family
Am J Physiol Gastrointest Liver Physiol 274: G607-G613, April 1998.
"The CCK and gastrin families of peptides act as hormones and neuropeptides on central and peripheral receptors to mediate secretion and motility in the gastrointestinal tract in the physiological response to a normal meal. Thus far, two CCK receptors have been molecularly identified to mediate the actions of CCK and gastrin, CCK-A and CCK-B receptors (CCK-AR and CCK-BR, respectively). The regulation of CCK-AR and CCK-BR affinity by guanine nucleotides and the receptor activation of G protein-dependent stimulation of phospholipase C and adenylyl cyclase suggested that they were guanine nucleotide-binding protein-coupled receptors [G protein-coupled receptors (GPCRs)]; however, the eventual cloning of their cDNAs revealed their heptahelical structure and confirmed their membership in the GPCR superfamily. The gastrointestinal system is a rich source of neuroendocrine hormones that interact with a large number of GPCRs to regulate the complex tasks of digestion, absorption, and excretion of a meal. This article focuses on the CCK family of GPCRs, and its activities in the gastrointestinal system." [Full Text]

Frankland, Paul W., Josselyn, Sheena A., Bradwejn, Jacques, Vaccarino, Franco J., Yeomans, John S.
Activation of Amygdala CholecystokininB Receptors Potentiates the Acoustic Startle Response in the Rat
J. Neurosci. 1997 17: 1838-1847
"The acoustic startle reflex is a sensitive index of "anxiety" and "fear." Potentiation of startle by conditioned and unconditioned fear stimuli appears to be mediated by the amygdala. CholecystokininB (CCKB) agonists increase "anxiety" in laboratory animals and induce "panic" in humans. Here, we investigate the role CCKB receptor-mediated mechanisms in the amygdala in the potentiation of startle. First, intra-amygdala infusions of the CCKB receptor agonist pentagastrin (0, 0.01, 0.1, 1, and 10 nM) produced a dose-related potentiation of acoustic startle responses. At the highest dose, startle amplitudes were increased up to 90% above preinfusion baseline levels. Second, similar infusions of pentagastrin had no effect on locomotor activity over the same time course, showing that increases in startle responsivity after infusions of pentagastrin are not attributable to nonspecific changes in motor activity. Third, infusions of similar doses of pentagastrin into the striatum or nucleus accumbens did not potentiate startle responses. Fourth, pretreatment with the CCKB receptor antagonist L-365,260 (0.1 mg/kg, i.p.) attenuated the potentiation of startle produced by intra-amygdala infusions of pentagastrin. Finally, intra-amygdala infusion of the CCKB receptor-selective antagonist PD-135158 (10 µg) blocked the potentiation of startle produced by i.c.v. infusions of pentagastrin, suggesting that i.c.v. infusions of pentagastrin potentiate startle responses via activation of amygdala CCKB receptors. These results show that amygdala CCKB receptor-mediated mechanisms are involved in the potentiation of acoustic startle responses." [Full Text]

Silvente-Poirot, Sandrine, Escrieut, Chantal, Wank, Stephen A.
Role of the Extracellular Domains of the Cholecystokinin Receptor in Agonist Binding
Mol Pharmacol 1998 54: 364-371 [Full Text]

Hommer, DW, Stoner, G, Crawley, JN, Paul, SM, Skirboll, LR
Cholecystokinin-dopamine coexistence: electrophysiological actions corresponding to cholecystokinin receptor subtype
J. Neurosci. 1986 6: 3039-3043
"Cholecystokinin (CCK)-like peptides when administered intravenously produce 2 distinct actions on the single-unit activity of mesencephalic dopamine (DA) neurons in the rat: an excitatory action and a potentiation of the inhibitory effects of DA agonists. The ability of several CCK fragments that have been shown to bind selectively to the peripheral and/or the central CCK-binding sites were examined for their ability to induce either excitation or a potentiation of DA. Only sulfated CCK-8 was able to induce excitation of mesencephalic DA neurons, but both sulfated and unsulfated CCK-8, as well as CCK-4, potentiated the inhibitory effects of the DA agonist apomorphine (APO). CCK-3 failed to potentiate APO-induced inhibition. Both of these effects appeared to be confined to cell bodies in regions of the ventral tegmental area and substantia nigra, zona compacta that have been reported to contain both DA and CCK. Thus, CCK-like peptides that have been shown to bind to the high-affinity CCK binding site in brain potentiated the effects of DA. In contrast, the ability of CCK-like peptides to induce neuronal excitation corresponds with their affinity for the peripheral-type CCK binding site." [Abstract]

Ni H, Xu L, Tang M, wang SB.
[A transient increase in CCK mRNA levels in amygdala following audiogenic seizures in audiogenic seizure-prone rats]
Sheng Li Xue Bao 2000 Apr 25;52(2):152-4
"The effects of single and multiple seizures on cholecystokinin (CCK) mRNA levels in amygdala of audiogenic seizure-prone rats (P77PMC) were examined by in situ hybridization. The main results are as follows: (1) CCK mRNA positive neurons (No/0.01 mm(2)) in amygdala showed a transient increase in number from the 8+/-1 to 58+/-5 (P<0.01) in 30 min and then returned to the control value in 2 h (9+/-2, P>0.05), and (2) in the multiple consecutive seizure rats the increase in 30 min (22+/-3) was less than that in the single seizure rats (P<0.01), and the number returned to normal in 1 h (6+/-1, P>0.05). These data indicate that the transient increase in CCK mRNA level in amygdala following single or multiple consecutive seizures of P77PMC may be involved in anti-convulsant mechanisms in response to acute seizures." [Abstract]

Zhang LJ, Lu XY, Han JS.
Influences of cholecystokinin octapeptide on phosphoinositide turnover in neonatal-rat brain cells.
Biochem J 1992 Aug 1;285 ( Pt 3):847-50
"Cholecystokinin octapeptide (CCK-8) has been shown to be coupled to phosphoinositide turnover in pancreatic acini as well as in a kind of neuroblastoma cell and a human embryonic cell line. Little is known, however, about its link with phosphatidylinositol breakdown in the brain. The brains (minus cerebella) from 1-2-day-old neonatal rats were enzymically dissociated into single cells. The intact cells were prelabelled by incubation with myo-[3H]inositol for 3 h, and were then stimulated with agonists in the presence of 10 mM-LiCl. Carbachol at 1 mM induced an increase in InsP3 labelling in brain cells (peak at 30 min, and then a gradual decrease), and a static accumulation of InsP with time, whereas the labelling of InsP2 remained essentially unchanged. A very similar time-response curve was obtained for 10 nM-CCK-8 in stimulating phosphoinositide turnover. The dose-response curve for incubated brain cells revealed that the formation of InsP3 increased when the concentration of CCK-8 was increased from 0.1 to 10 nM. A further increase in CCK-8 concentration to 100-1000 nM resulted in a gradual decrease in InsP3 formation. InsP and InsP2 levels stayed relatively stable. The production of InsP3 stimulated by 10 nM-CCK-8 was dose-dependently suppressed by the CCK-A antagonist Devazepide in the concentration range 1-10 nM; the effect declined when the concentration was further increased to 100-1000 nM. In contrast, the CCK-B antagonist L365,260 showed a sustained suppression of InsP3 production at concentrations above 0.1 nM, i.e. in the range 1-1000 nM. The results provide evidence that CCK-8 stimulates the turnover of phosphoinositide and increases InsP3 labelling in dissociated neonatal-rat brain cells, in which both CCK-A and CCK-B receptors seem to be involved." [Abstract]

Carter DA, Lightman SL.
A role for the area postrema in mediating cholecystokinin-stimulated oxytocin secretion.
Brain Res 1987 Dec 1;435(1-2):327-30 [Abstract]

Depot M, Caille G, Mukherjee J, Katzman MA, Cadieux A, Bradwejn J.
Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans.
Neuropsychopharmacology 1999 Feb;20(2):177-87 [Abstract]

Zhi-Jie Cheng, and Laurence J. Miller
Agonist-dependent Dissociation of Oligomeric Complexes of G Protein-coupled Cholecystokinin Receptors Demonstrated in Living Cells Using Bioluminescence Resonance Energy Transfer
J. Biol. Chem. 276: 48040-48047, December 2001. [Full Text]

Geier, Elke, Pfeifer, Günter, Wilm, Matthias, Lucchiari-Hartz, Maria, Baumeister, Wolfgang, Eichmann, Klaus, Niedermann, Gabriele
A Giant Protease with Potential to Substitute for Some Functions of the Proteasome
Science 1999 283: 978-981
"An alanyl-alanyl-phenylalanyl-7-amino-4-methylcoumarin-hydrolyzing protease particle copurifying with 26S proteasomes was isolated and identified as tripeptidyl peptidase II (TPPII), a cytosolic subtilisin-like peptidase of unknown function. The particle is larger than the 26S proteasome and has a rod-shaped, dynamic supramolecular structure. TPPII exhibits enhanced activity in proteasome inhibitor-adapted cells and degrades polypeptides by exo- as well as predominantly trypsin-like endoproteolytic cleavage. TPPII may thus participate in extralysosomal polypeptide degradation and may in part account for nonproteasomal epitope generation as postulated for certain major histocompatibility complex class I alleles. In addition, TPPII may be able to substitute for some metabolic functions of the proteasome." [Full Text]

Billig I, Yates BJ, Rinaman L.
Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin.
Am J Physiol Regul Integr Comp Physiol 2001 Oct;281(4):R1243-55
"Posterior pituitary hormone secretion and central neural expression of the immediate-early gene product c-Fos was examined in adult ferrets after intravenous administration of CCK octapeptide. Pharmacological doses of CCK (1, 5, 10, or 50 microg/kg) did not induce emesis, but elicited behavioral signs of nausea and dose-related increases in plasma vasopressin (AVP) levels without significant increases in plasma oxytocin (OT) levels. CCK activated neuronal c-Fos expression in several brain stem viscerosensory regions, including a dose-related activation of neurons in the dorsal vagal complex (DVC). Activated brain stem neurons included catecholaminergic and glucagon-like peptide-1-positive cells in the DVC and ventrolateral medulla. In the forebrain, activated neurons were prevalent in the paraventricular and supraoptic nuclei of the hypothalamus and also were observed in the central nucleus of the amygdala and bed nucleus of the stria terminalis. Activated hypothalamic neurons included cells that were immunoreactive for AVP, OT, and corticotropin-releasing factor. Comparable patterns of brain stem and forebrain c-Fos activation were observed in ferrets after intraperitoneal injection of lithium chloride (LiCl; 86 mg/kg), a classic emetic agent. However, LiCl activated more neurons in the area postrema and fewer neurons in the nucleus of the solitary tract compared with CCK. Together with results from previous studies in rodents, our findings support the view that nauseogenic treatments activate similar central neural circuits in emetic and nonemetic species, despite differences in treatment-induced emesis and pituitary hormone secretion." [Abstract]

Facchinetti P, Rose C, Rostaing P, Triller A, Schwartz JC.
Immunolocalization of tripeptidyl peptidase II, a cholecystokinin-inactivating enzyme, in rat brain.
Neuroscience 1999;88(4):1225-40
"Tripeptidyl peptidase II (EC is a serine peptidase apparently involved in the inactivation of cholecystokinin octapeptide [Rose C. et al. (1996) Nature 380, 403-409]. We have compared its distribution with that of cholecystokinin in rat brain, using a polyclonal antibody raised against a highly purified preparation for immunohistochemistry at the photon and electron microscope levels. Tripeptidyl peptidase II-like immunoreactivity was mostly detected in neurons, and also in ependymal cells and choroid plexuses, localizations consistent with a possible participation of the peptidase in the inactivation of cholecystokinin circulating in the cerebrospinal fluid. Immunoreactivity was mostly detected in cell bodies, large processes and, to a lesser extent, axons of various neuronal populations. Their localization, relative to that of cholecystokinin terminals, appears to define three distinct situations. The first corresponds to neurons with high immunoreactivity in areas containing cholecystokinin terminals, as in the cerebral cortex or hippocampal formation, where pyramidal cell bodies and processes surrounded by cholecystokinin axons were immunoreactive. A similar situation was encountered in many other areas, namely along the pathways through which cholecystokinin controls satiety, i.e. in sensory vagal neurons, the nucleus tractus solitarius and hypothalamic nuclei. The second situation corresponds to cholecystokinin neuronal populations containing tripeptidyl peptidase II-like immunoreactivity, as in neurons of the supraoptic or paraventricular nuclei, axons in the median eminence or nigral neurons. In both situations, localization of tripeptidyl peptidase II-like immunoreactivity is consistent with a role in cholecystokinin inactivation. The third situation corresponds to areas with mismatches, such as the cerebellum, a region devoid of cholecystokinin, but in which Purkinje cells displayed high tripeptidyl peptidase II-like immunoreactivity, possibly related to a role in the inactivation of neuropeptides other than cholecystokinin. Also, some areas with cholecystokinin terminals, e.g., the molecular layer of the cerebral cortex, were devoid of tripeptidyl peptidase II-like immunoreactivity, suggesting that processes other than cleavage by tripeptidyl peptidase II may be involved in cholecystokinin inactivation. Tripeptidyl peptidase II-like immunoreactivity was also detected at the ultrastructural level in the cerebral cortex and hypothalamus using either immunoperoxidase or silver-enhanced immunogold detection. It was mainly associated with the cytoplasm of neuronal somata and dendrites, often in the vicinity of reticulum cisternae, Golgi apparatus or vesicles, and with the inner side of the dendritic plasma membrane. Hence, whereas a fraction of tripeptidyl peptidase II-like immunoreactivity localization at the cellular level is consistent with its alleged function in cholecystokinin octapeptide inactivation, its association with the outside plasma membrane of neurons remains to be confirmed." [Abstract]

Rose C, Vargas F, Facchinetti P, Bourgeat P, Bambal RB, Bishop PB, Chan SM, Moore AN, Ganellin CR, Schwartz JC.
Characterization and inhibition of a cholecystokinin-inactivating serine peptidase.
Nature 1996 Apr 4;380(6573):403-9
"A cholecystokinin (CCK)-inactivating peptidase was purified and identified as a membrane-bound isoform of tripeptidyl peptidase II (EC, a cytosolic subtilisin-like peptidase of previously unknown functions. The peptidase was found in neurons responding to cholecystokinin, as well as in non-neuronal cells. Butabindide, a potent and specific inhibitor, was designed and shown to protect endogenous cholecystokinin from inactivation and to display pro-satiating effects mediated by the CCKA receptor." [Abstract]

Macpherson E, Tomkinson B, Balow RM, Hoglund S, Zetterqvist O.
Supramolecular structure of tripeptidyl peptidase II from human erythrocytes as studied by electron microscopy, and its correlation to enzyme activity.
Biochem J 1987 Nov 15;248(1):259-63
"Tripeptidyl peptidase II is an extralysosomal serine peptidase of an unusually large size, i.e. Mr greater than 10(6) for the native enzyme and Mr 135000 for the subunit. The enzyme from human erythrocytes was studied by electron microscopy on samples negatively stained by ammonium molybdate. Two different structural representations of the purified enzyme were obtained, both with a length of about 50 nm, and consisting of repetitive substructures. Upon dialysis of the enzyme against a Tris/HCl buffer, the activity was gradually decreased. This decrease was shown to parallel the dissociation of the large enzyme structures into smaller ones, the smallest measuring 3 nm by 10 nm and apparently corresponding to the repetitive substructures. The results indicate that a large polymeric form of the enzyme is a prerequisite for full activity." [Abstract]

Tomkinson B, Nyberg F.
Distribution of tripeptidyl-peptidase II in the central nervous system of rat.
Neurochem Res 1995 Dec;20(12):1443-7
"Tripeptidyl-peptidase II (TPP II) is a high molecular weight serine peptidase which removes tripeptides from a free N-terminus of longer peptides. Since it had previously been demonstrated that the enzyme can inactivate enkephalins and dynorphins in vitro by removing the N-terminal Tyr-Gly-Gly peptide, we wanted to see whether TPP II could be involved in this process also in vivo. Therefore, the localization of TPP II in different cerebral regions of rat was investigated by immunoblot analysis and activity measurements. It could be shown that TPP II is relatively evenly distributed in the central nervous system of rat. This indicates that the physiological role of the enzyme is probably not a specific degradation of enkephalins, but rather pertains to the general turnover of proteins." [Abstract]

Noble, Florence, Wank, Stephen A., Crawley, Jacqueline N., Bradwejn, Jacques, Seroogy, Kim B., Hamon, Michel, Roques, Bernard P.
International Union of Pharmacology. XXI. Structure, Distribution, and Functions of Cholecystokinin Receptors
Pharmacol Rev 1999 51: 745-781
"The actions of CCK and related peptides have been extended to include endocrine secretion; motility and growth in the gastrointestinal system; and regulation of satiety, anxiety, pain, and dopamine-mediated behavior in the central and peripheral nervous systems. These actions are mediated by at least two distinct receptors, which have been pharmacologically characterized. The existence of these CCK receptors (CCK1 and CCK2) has subsequently been confirmed by their molecular cloning. Nevertheless, the large variety of functions mediated by CCK receptors, as well as pharmacological studies, suggests that some heterogeneity exists in CCK1 and CCK2 receptors. However, such a heterogeneity has not been confirmed in molecular biology studies, which have so far identified only two members of the CCK receptor family." [Full Text]

Mo N, Dun NJ.
Cholecystokinin octapeptide depolarizes guinea pig inferior mesenteric ganglion cells and facilitates nicotinic transmission.
Neurosci Lett 1986 Mar 14;64(3):263-8
"Cholecystokinin octapeptide (CCK-8) applied either by superfusion (0.1-10 microM) or by pressure ejection elicited a slow depolarization in a portion of inferior mesenteric ganglion cells studied in vitro. The depolarization which persisted in a low Ca2+/high Mg2+ solution, or solution containing cholinergic antagonists, was often associated with a small to moderate increase in neuronal input resistance, and the response was reduced by conditioning hyperpolarization. Nicotinic excitatory postsynaptic potentials were consistently augmented during the course of CCK-8-induced depolarization. Our results, together with findings of the presence of CCK-immunoreactive fibers in the prevertebral ganglia, suggest that the peptide may serve to facilitate nicotinic transmission." [Abstract]

You, ZB, Herrera-Marschitz, M, Brodin, E, Meana, JJ, Morino, P, Hokfelt, T, Silveira, R, Goiny, M, Ungerstedt, U
On the origin of striatal cholecystokinin release: studies with in vivo microdialysis.
J Neurochem 1994 62: 76-85
"In the present study, extracellular levels of the neuropeptide cholecystokinin (CCK), of the monoamine dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and of the excitatory amino acids glutamate and aspartate were simultaneously monitored by microdialysis in the neostriatum of halothane-anesthetized rats under basal and K(+)-depolarizing conditions. Extracellular CCK and dopamine levels, but not glutamate and aspartate levels, were decreased by perfusion with a Ca(2+)-free medium, under both basal and K(+)-depolarizing conditions. HPLC revealed that the majority of the CCK-like immunoreactivity in the perfusates coeluted with CCK octapeptide. Striatal extracellular CCK levels were decreased by decortication plus callosotomy, with a parallel decrease in glutamate levels. Striatal extracellular levels of dopamine, DOPAC, and HVA were significantly decreased in animals treated previously with a unilateral 6-hydroxydopamine injection into the medial forebrain bundle. In these animals, however, the effect of decortication plus callosotomy on CCK and glutamate levels was not further augmented. Thus, this study supports the hypothesis of a neuronal origin of extracellular CCK and dopamine monitored with microdialysis in the striatum of the rat, and also supports the idea of a partly contralateral origin of corticostriatal CCK and glutamate inputs." [Abstract]

Schiffmann SN, Vanderhaeghen JJ.
Lesion of the nigrostriatal pathway induces cholecystokinin messenger RNA expression in the rat striatum. An in situ hybridization histochemistry study.
Neuroscience 1992 Oct;50(3):551-7
"In situ hybridization histochemistry was used to investigate the putative regulation of cholecystokinin messenger RNA expression by dopamine in the rat striatum. Using this method, cholecystokinin messenger RNA was undetectable in the normal rat striatum. Dopamine depletion caused by a 6-hydroxydopamine injection in the medical forebrain bundle induced, two and four weeks after the injection, an increase of cholecystokinin messenger RNA expression in the ipsilateral striatum. The labeling was mostly restricted to the dorsolateral quadrant. At the cellular level, this corresponded to a slight but significant labeling of a moderate density of striatal neurons which most probably represent a subpopulation of medium-sized spiny neurons. Conversely, treatment with either haloperidol or SCH23390 for two weeks did not induce any detectable changes in cholecystokinin messenger RNA expression in the striatum while, as expected, an increase in the striatal enkephalin messenger RNA content was observed. These results suggest that the dopaminergic nigrostriatal pathway directly, or indirectly, regulates the expression of cholecystokinin messenger RNA in the striatum." [Abstract]

Artaud F, Baruch P, Stutzmann JM, Saffroy M, Godeheu G, Barbeito L, Herve D, Studler JM, Glowinski J, Cheramy A.
Cholecystokinin: Corelease with dopamine from nigrostriatal neurons in the cat.
Eur J Neurosci 1989 Mar;1(2):162-171
"Halothane-anaesthetized cats were implanted with push-pull cannulae to demonstrate the in vivo release of cholecystokinin-like immunoreactivity (CCK-LI) in the substantia nigra and the ipsilateral caudate nucleus. The spontaneous and the calcium-dependent potassium-evoked release of CCK-LI were observed in both structures. In addition, the local application of tetrodotoxin (10-6 M) reduced the spontaneous release of the peptide. 6-OHDA lesions made in the substantia nigra pars compacta led to a complete destruction of nigrostriatal dopaminergic neurons. CCK-LI levels were not affected in the caudate nucleus but were reduced substantially in the substantia nigra. The activation of dopaminergic cells induced by the nigral application of alpha-methyl-para-tyrosine (10-4 M) stimulated the release of CCK-LI and dopamine in the ipsilateral caudate nucleus, whilst opposite effects were seen in the substantia nigra. Similar results were obtained when dopaminergic transmission was blocked in the caudate nucleus suggesting that the evoked release of CCK-LI by the alpha-methyl-para-tyrosine treatment originates from dopaminergic nerve terminals and not from other CCK-LI containing fibres in response to released dopamine. Dopamine (10-7 M) as well as the D1 agonist SKF 38393 (10-5 M) stimulated CCK-LI release when applied into the caudate nucleus while the D2 agonist, LY 171555 (10-6 M) slightly reduced peptide release. The local application of cholecystokinin-8 sulfate (CCK-8S) (10-8 M, for 30 min) into the substantia nigra pars compacta increased the firing rate of dopaminergic cells and stimulated the release of newly synthesized 3H-dopamine from dendrites and nerve terminals. These results suggest, but do not definitively prove, that, in the cat, CCK-LI and dopamine are coreleased from nigrostriatal mixed dopaminergic/CCK-LI neurons and that CCK-LI released from dendrites is, like dopamine, involved in the regulation of the activity of these cells." [Abstract]

Crawley JN, Corwin RL.
Biological actions of cholecystokinin.
Peptides 1994;15(4):731-55
"Cholecystokinin (CCK) has emerged as an important mammalian neuropeptide, localized in peripheral organs and in the central nervous system. This review presents an overview of the molecular aspects of CCK peptides and CCK receptors, the anatomical distribution of CCK, the neurophysiological actions of CCK, release of CCK and effects of CCK on release of other neurotransmitters, and the actions of CCK on digestion, feeding, cardiovascular function, respiratory function, neurotoxicity and seizures, cancer cell proliferation, analgesia, sleep, sexual and reproductive behaviors, memory, anxiety, and dopamine-mediated exploratory and rewarded behaviors. Human clinical studies of CCK in feeding disorders and panic disorders are described. New findings are presented on potent, nonpeptide CCK antagonists, selective for the two CCK receptor subtypes, which demonstrate that endogenous CCK has biologically important effects on physiology and behavior." [Abstract]

Wang ZJ, Rao ZR, Shi JW.
Tyrosine hydroxylase-, neurotensin-, or cholecystokinin-containing neurons in the nucleus tractus solitarii send projection fibers to the nucleus accumbens in the rat.
Brain Res 1992 Apr 24;578(1-2):347-50 [Abstract]

Paudice, P, Raiteri, M
Cholecystokinin release mediated by 5-HT3 receptors in rat cerebral cortex and nucleus accumbens
Br. J. Pharmacol. 1991 103: 1790-1794
"It is concluded that 5-HT can act as a potent releaser of CCK-LI in rat cerebrocortex and nucleus accumbens through the activation of receptors of the 5-HT3 type situated on the CCK-releasing terminals. This interaction may provide a rationale for the clinical development of both 5-HT3 and CCK receptor antagonists as novel anxiolytic drugs." [Article]

Morales, Marisela, Bloom, Floyd E.
The 5-HT3 Receptor Is Present in Different Subpopulations of GABAergic Neurons in the Rat Telencephalon
J. Neurosci. 1997 17: 3157-3167
"To analyze further the role of the 5-HT3R in the CNS, we used in situ hybridization and immunocytochemistry to determine that 5-HT3R-expressing neurons are mainly GABA-containing cells in the rat telencephalon. We determined that 5-HT3R/GABA-containing neurons do not exhibit somatostatin immunoreactivity but often contain cholecystokinin (CCK) immunoreactivity. 5-HT3R-expressing cells with CCK immunoreactivity were observed in the neocortex, olfactory cortex, hippocampus, and amygdala. The 5-HT3R/CCK interneurons represent between 35 and 66% of the total population of CCK-containing cells in the neocortex." [Full Text]

Crawley JN.
Cholecystokinin accelerates the rate of habituation to a novel environment.
Pharmacol Biochem Behav 1984 Jan;20(1):23-7
"Cholecystokinin (CCK8), an octapeptide present in high concentrations in both gut and brain, has been proposed as a putative satiety signal in a variety of species. Exploratory and social behaviors in particular are inhibited by exogenously administered CCK8. One hypothesis for the mechanism by which CCK reduces feeding and exploration is that CCK8 is reducing arousal and attention to environmental stimuli. This possibility was tested by analyzing the rate of habituation to the novelty of objects placed in an unfamiliar arena. A video-tracking computer-assisted animal behavior monitor measured four parameters of exploratory behaviors in rats pretreated with intraperitoneal CCK8. During the first 30 minutes in the novel environment, CCK8-treated animals showed a reduced latency to cessation of exploration as compared to saline controls. In repeated five minute sessions on consecutive days, CCK8 treatment accelerated the decline in exploration over daily sessions. Pentobarbital, a known sedative, induced low levels of exploration throughout the repeated daily sessions. These data suggest that CCK8 is inducing a more rapid rate of habituation to the novelty of environmental stimuli. An accelerated rate of habituation might underlie some of the satiety-related behavioral effects of this peptide." [Abstract]

Dauge V, Dor A, Feger J, Roques BP.
The behavioral effects of CCK8 injected into the medial nucleus accumbens are dependent on the motivational state of the rat.
Eur J Pharmacol 1989 Apr 12;163(1):25-32
"The effects of CCK8 injected into the rat median nucleus accumbens on exploration and locomotion were measured in the four hole box and open-field tests. CCK8 (1 fmol to 100 pmol) induced hypoexploration in the four hole box (duration, frequency), with the pattern of the responses remaining unchanged compared to those of the control group. These effects were reversed by injection of the CCK antagonist proglumide (20 micrograms) into the nucleus accumbens. In the open-field test, CCK8 (100 pmol) only decreased locomotion and rearing when the rats were not habituated to the environment. These results show that the behavior of rats exposed to a novel external stimuli is highly sensitive to CCK8." [Abstract]

Tomkinson B, Grehn L, Fransson B, Zetterqvist O.
Use of a dehydroalanine-containing peptide as an efficient inhibitor of tripeptidyl peptidase II.
Arch Biochem Biophys 1994 Nov 1;314(2):276-9
"Tripeptidyl peptidase II is an intracellular exopeptidase, which has been purified from rat liver and human erythrocytes. An efficient specific inhibitor was obtained through beta-elimination of phosphate from the phosphopeptide Arg-Ala-Ser(P)-Val-Ala. The dehydroalanine-containing peptide formed was a competitive inhibitor with a Ki of 0.02 +/- 0.01 microM. This study demonstrated that replacing a serine residue in a good inhibitor with a dehydroalanine residue reduced the Ki 45 times." [Abstract]

The New Biology of Gastrointestinal Hormones
Physiol. Rev. 1998 78: 1087-1108
"The new biology suggests that gastrointestinal hormones should be conceived as intercellular messengers of general physiological impact rather than as local regulators of the upper digestive tract." [Full Text]

Zachrisson O, Mathe AA, Lindefors N.
Effects of chronic lithium and electroconvulsive stimuli on cholecystokinin mRNA expression in the rat brain.
Brain Res Mol Brain Res 1996 Dec 31;43(1-2):347-50
"This study compares the effect of lithium (Li+) and electroconvulsive stimuli (ECS), two treatments commonly used in the treatment of affective disorders, on CCK mRNA expression in the rat brain. Two groups of rats receiving either 4 week Li+ or vehicle food supplementation and two groups receiving 6 ECS or 6 sham ECS during 2 weeks were studied. A significant decrease in CCK mRNA levels was seen in the caudate putamen both after Li+ as compared to vehicle and ECS as compared to sham ECS, 27 and 25%, respectively. A small (10%), yet significant, decrease was also seen in the inner entorhinal cortex after Li+. The results indicate that both Li+ and ECS inhibit CCK synthesis in the caudate putamen and are consistent with other findings of presumed decreased dopaminergic action in this part of the brain following these treatments." [Abstract]

Xie JX, Tang M, Zhang C.
Effect of cholecystokinin-8 microinjection into ventral tegmental area on dopamine release in nucleus accumbens of rats: an in vivo voltammetric study.
Prog Neuropsychopharmacol Biol Psychiatry 2001 Feb;25(2):427-34
"1. Effects of microinjection of cholecystokinin-8 (CCK-8) into the rat ventral tegmental area were studied on dopamine (DA) release from nucleus accumbens (Acb), using fast cyclic voltammetry and carbon fibre microelectrode. 2. DA release was evoked by electrical stimulation of the medial forebrain bundle (MFB). DA release from Acb was increased with increasing intensity or frequency of electrical stimulation in a dose-dependent manner and was inhibited by microinjection of CCK-8 (0.5 microg/kg) into the ventral tegmental area. 3. The release of DA was clearly reduced at all the intensities (0.25, 0.5, 0.75 and 1.0 mA) tested following CCK injection into the VTA, which was statistically significant (P<0.05). But the reduced percentage of DA release did not show significant changes between the data obtained with stimuli of different intensities (P>0.05). 4. While no change could be found with the stimuli of 10Hz, the DA release was significantly suppressed by injection of CCK-8 at the other three frequencies tested (50 Hz, 100 Hz and 250 Hz). Furthermore, although the differences in the reduced amounts of DA release obtained at 50 Hz, 100 Hz and 250 Hz were statistically significant, the reduced percentage seemed to be not closely related to the frequency applied (P>0.05). 5. These results indicate that CCK-8 is involved in the regulation of midbrain DA neurotransmission, and thereby implicated in disorders, such as Parkinson's disease, that involve malfunctions of the basal ganglion DA neuronal systems." [Abstract]

L Buscail, J Esteve, N Saint-Laurent, V Bertrand, T Reisine, A O'Carroll, GI Bell, AV Schally, N Vaysse, and C Susini
Inhibition of Cell Proliferation by the Somatostatin Analogue RC-160 is Mediated by Somatostatin Receptor Subtypes SSTR2 and SSTR5 Through Different Mechanisms
PNAS 92: 1580-1584.
"Cell proliferation was induced in CHO cells by 10% (vol/vol) fetal calf serum, 1 µM insulin, or 0.1 µM cholecystokinin (CCK)-8; RC-160 inhibited serum-induced proliferation of CHO cells expressing SSTR2 and SSTR5 (EC50, 53 and 150 pM, respectively) but had no effect on growth of cells expressing SSTR1, -3, or -4. In SSTR2-expressing cells, orthovanadate suppressed the growth inhibitory effect of RC-160. This analogue inhibited insulin-induced proliferation and rapidly stimulated the activity of a tyrosine phosphatase in only this cellular clone. This latter effect was observed at doses of RC-160 (EC50, 4.6 pM) similar to those required to inhibit growth (EC50, 53 pM) and binding to the receptor (IC50, 170 pM), implicating tyrosine phosphatase as a transducer of the growth inhibition signal in SSTR2-expressing cells. In SSTR5-expressing cells, the phosphatase pathway was not involved in the inhibitory effect of RC-160 on cell growth, since this action was not influenced by tyrosine and serine/threonine phosphatase inhibitors. In addition, in SSTR5-expressing cells, RC-160 inhibited CCK-stimulated intracellular calcium mobilization at doses (EC50, 0.35 nM) similar to those necessary to inhibit somatostatin-14 binding (IC50, 21 nM) and CCK-induced cell proliferation (EC50, 1.1 nM). This suggests that the inositol phospholipid/calcium pathway could be involved in the antiproliferative effect of RC-160 mediated by SSTR5 in these cells. RC-160 had no effect on the basal or carbachol-stimulated calcium concentration in cells expressing SSTR1 to -4. Thus, we conclude that SSTR2 and SSTR5 bind RC-160 with high affinity and mediate the RC-160-induced inhibition of cell growth by distinct mechanisms." [Abstract/Full Text]

Smadja C, Maldonado R, Turcaud S, Fournie-Zaluski MC, Roques BP.
Opposite role of CCKA and CCKB receptors in the modulation of endogenous enkephalin antidepressant-like effects.
Psychopharmacology (Berl) 1995 Aug;120(4):400-8
"Systemic administration of RB 101, a complete inhibitor of the enkephalin degrading enzymes, has been reported to induce naltrindole-reversed antidepressant-like effects in the conditioned suppression of motility (CSM) test in mice. The selective CCKB antagonist L-365,260 also elicits the same naltrindole-blocked responses on CSM. The aim of this study was therefore to investigate the possible modulation of RB 101 induced behavioral responses by activation or blockade of CCK receptors. Thus, the effects induced by RB 101 administered alone or associated with an ineffective dose of a selective CCKB agonist (BC 264), a CCKB antagonist (L-365,260) or a CCKA antagonist (L-364,718), were evaluated on the CSM in mice. RB 101 alone decreased the stress-induced loss of motility, as previously reported. The antidepressant-like effect of RB 101 was potentiated by L-365,260, and suppressed by BC 264 and to a lesser extent by L-364,718. The facilitatory effect induced by L-365,260 on RB 101 responses was blocked by the delta selective antagonist naltrindole. All these effects occurred only in shocked animals. The present results suggest that the activation of CCKA and CCKB receptors by endogenous CCK, could play an opposite role in the control of behavioral responses induced by endogenous enkephalins. Delta opioid receptors seem to be selectively involved in this interaction." [Abstract]

O'Neill MF, Dourish CT, Iversen SD.
Hypolocomotion induced by peripheral or central injection of CCK in the mouse is blocked by the CCKA receptor antagonist devazepide but not by the CCKB receptor antagonist L-365,260.
Eur J Pharmacol 1991 Feb 7;193(2):203-8
"The pharmacological mechanisms underlying the hypolocomotion induced by intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injections of cholecystokinin octapeptide sulphated (CCK) in the mouse were examined using selective CCKA and CCKB receptor antagonists. Locomotor activity was measured in photocell cages. CCK (10 micrograms/kg i.p.) significantly reduced activity in mice tested in the afternoon but not in the morning, indicating a circadian variation in the effect of the peptide. The hypolocomotion induced by i.p. injection of 10 micrograms/kg CCK and i.c.v. injection of 3.5 micrograms CCK was reversed by the selective CCKA antagonist devazepide, but not by the selective CCKB antagonist L-365,260. This suggests that CCK-induced hypolocomotion is mediated by CCKA receptors. Larger doses of CCK were required to induce hypolomotion when injected i.c.v. (3.5 micrograms per mouse) than when given i.p. (10 micrograms/kg i.e. 0.2 microgram per mouse). Furthermore the latency to onset of the hypolocomotion after i.c.v. injection of CCK was longer than after i.p. injection of CCK. These data suggest that the sedative action of i.c.v. CCK may be due to leakage of the peptide from the brain and subsequent activation of peripheral CCKA receptors. However a role for CCKA receptors in the CNS in mediating hypolocomotion induced by i.c.v. injection of CCK cannot be ruled out on the basis of the present data." [Abstract]

Lavigne GJ, Millington WR, Mueller GP.
The CCK-A and CCK-B receptor antagonists, devazepide and L-365,260, enhance morphine antinociception only in non-acclimated rats exposed to a novel environment.
Neuropeptides 1992 Feb;21(2):119-29
"Devazepide, a potent CCK-A receptor antagonist, and L-365,260, a selective CCK-B receptor antagonist, have been introduced as pharmacologic tools for differentiating the physiologic roles of CCK-A and CCK-B receptor subtypes. In the present study, we tested the effects of devazepide and L-365,260, on morphine antinociception in rats using the thermal sensorimotor tail flick test. Both devazepide and L-365,260 significantly enhanced the antinociceptive action of morphine, but only in rats that had not been acclimated to the laboratory environment or habituated to investigator handling. When tested with fully acclimated animals, devazepide and L-365,260 had no effect whatsoever; they neither enhanced nor attenuated morphine-induced antinociception. These observations indicate that the effects of devazepide and L-365,260, CCK antagonists, on morphine antinociception appear to be dependent on the animal's response to a new environment or to the stress induced by an unaccustomed experimental paradigm." [Abstract]

Harro J, Oreland L.
Cholecystokinin receptors and memory: a radial maze study.
Pharmacol Biochem Behav 1993 Mar;44(3):509-17
"CCK receptor agonists and antagonists have repeatedly been demonstrated to improve and impair, respectively, learning and memory functions. However, all studies to date have exploited avoidance paradigms. In the present study, the effect of some CCK receptor agonists and antagonists on the ability to learn an appetitively motivated task and to influence spatial working memory was investigated. In the first experiment, drugs were given immediately after each training session in the radial maze and the animals were tested, drug-free, during a 2-week period. After the initial treatments with caerulein, an unselective CCK receptor agonist (100 ng/kg SC), the animals were slightly less successful to obtain food pellets during the sessions on the first 2 days; whereas proglumide, an unselective CCK receptor antagonist (1 mg/kg SC) was without any effect. However, on the following days, all the three groups of rats (saline, caerulein, and proglumide) performed in a similar way. In the second experiment, drugs were given before each test session to well-trained animals. Scopolamine (0.15 and 0.3 mg/kg IP), the reference amnestic drug, produced dose-dependent impairment of working memory in the radial maze test. Proglumide (1 and 10 mg/kg SC) and devazepide, (a selective CCK-A receptor antagonist; 0.01 and 1 mg/kg SC), as well as caerulein (0.01, 0.1 and 1 microgram/kg SC) and CCK-4 (a selective CCK-B receptor agonist; 25 and 50 micrograms/kg SC) had no reliable effect." [Abstract]

Dodt C, Sarnighausen HE, Pietrowsky R, Fehm HL, Born J.
Ceruletide improves event-related potential indicators of cognitive processing in young but not in elderly humans.
J Clin Psychopharmacol 1996 Dec;16(6):440-5
"The effect of intravenously administered ceruletide, a cholecystokinin (CCK) analogue, on neurophysiologic signs of stimulus processing was tested in 16 young (19-28 years) and 16 aged (70-86 years) healthy subjects. Placebo or 2.5 micrograms ceruletide was infused within 30 minutes according to a double-blind within-subject crossover design. Thereafter, auditory event-related brain potential (AERP) responses to stimuli of an "oddball" task (including the random presentation of frequent standard tones and rare target tones) were recorded. Amplitudes of the P2, P3, and SW components of the AERP were reduced in aged subjects (p < 0.05, p < 0.001, and p < 0.01, respectively), and latencies (from stimulus onset) of the N2 and P3 components were prolonged (p < 0.05 and p < 0.01, respectively). Together, these changes indicate impaired cognitive processing capabilities in aged compared with young subjects. Ceruletide enhanced P3 and also the subsequent slow-wave (SW) component that occurs 500 to 700 ms poststimulus in young subjects (p < 0.05 and p < 0.001, respectively). The peptide did not at all affect AERPs in the elderly subjects. Results demonstrate the capability of ceruletide after systemic administration to enhance central nervous system indicators of cognitive processing such as P3 and SW in young subjects. However, despite the clear effect of the CCK analogue in young subjects, it remained ineffective in the group of aged subjects and, thus, failed to compensate for the decline in AERP signs of working memory functioning in the elderly subjects." [Abstract]

Mauri MC, Rudelli R, Vanni S, Panza G, Sicaro A, Audisio D, Sacerdote P, Panerai AE.
Cholecystokinin, beta-endorphin and vasoactive intestinal peptide in peripheral blood mononuclear cells of drug-naive schizophrenic patients treated with haloperidol compared to healthy controls.
Psychiatry Res 1998 Mar 20;78(1-2):45-50
"Cholecystokinin (CCK), beta-endorphin (BE), and vasoactive intestinal peptide (VIP) in peripheral blood mononuclear cells from 30 drug-naive schizophrenics compared to 22 healthy controls were studied. Patients were evaluated with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of the Negative Symptoms (SANS) at baseline (TO), and after four weeks (T4) in nine patients who were subsequently treated with haloperidol (HL). Neuropeptide concentrations in peripheral blood mononuclear cells (PBMC) were measured at TO and, for the treated patients, at T4. There was a negative correlation between CCK and SANS baseline scores and a trend for patients who responded poorly to HL (i.e. patients with a prevalence of negative symptomatology) to have lower CCK basal values." [Abstract]

Tomkinson, Birgitta, Ni Laoi, Bairbre, Wellington, Kimberly
The insert within the catalytic domain of tripeptidyl-peptidase II is important for the formation of the active complex
Eur J Biochem 2002 269: 1438-1443
"Tripeptidyl-peptidase II (TPP II) is a large (M r >106 ) tripeptide-releasing enzyme with an active site of the subtilisin-type. Compared with other subtilases, TPP II has a 200 amino-acid insertion between the catalytic Asp44 and His264 residues, and is active as an oligomeric complex. This study demonstrates that the insert is important for the formation of the active high-molecular mass complex. A recombinant human TPP II and a murine TPP II were found to display different complex-forming characteristics when over-expressed in human 293-cells; the human enzyme was mainly in a nonassociated, inactive state whereas the murine enzyme formed active oligomers. This was surprising because native human TPP II is purified from erythrocytes as an active oligomeric complex, and the amino-acid sequences of the human and murine enzymes were 96% identical. Using a combination of chimeras and a single point mutant, the amino acid responsible for this difference was identified as Arg252 in the recombinant human sequence, which corresponds to a glycine in the murine sequence. As Gly252 is conserved in all sequenced variants of TPP II, the recombinant enzyme with Arg252 is atypical. Nevertheless, as Arg252 evidently interferes with complex formation, and this residue is close to the catalytic His264, it may also explain why oligomerization influences enzyme activity. The exact mechanism for how the G252R substitution interferes with complex formation remains to be determined, but will be of importance for the understanding of the unique properties of TPP II." [Abstract]

You, Zhi-Bing, Tzschentke, Thomas M., Brodin, Ernst, Wise, Roy A.
Electrical Stimulation of the Prefrontal Cortex Increases Cholecystokinin, Glutamate, and Dopamine Release in the Nucleus Accumbens: an In Vivo Microdialysis Study in Freely Moving Rats
J. Neurosci. 1998 18: 6492-6500
"In vivo microdialysis, radioimmunoassay, and HPLC with electrochemical or fluorometric detection were used to investigate the release of cholecystokinin (CCK), glutamate (Glu), and dopamine (DA) in nucleus accumbens septi (NAS) as a function of ipsilateral electrical stimulation of medial prefrontal cortex (mPFC). CCK was progressively elevated by mPFC stimulation at 50-200 Hz. Stimulation-induced CCK release was intensity-dependent at 250-700 µA. NAS Glu and DA levels were each elevated by stimulation at 25-400 Hz; the dopamine metabolites DOPAC and homovanillic acid were increased by stimulation at 100-400 Hz. When rats were trained to lever press for mPFC stimulation, the stimulation induced similar elevations of each of the three transmitters to those seen with experimenter-administered stimulation. Perfusion of 1 mM kynurenic acid (Kyn) into either the ventral tegmental area (VTA) or NAS blocked lever pressing for mPFC stimulation. VTA, but not NAS, perfusion of Kyn significantly attenuated the increases in NAS DA levels induced by mPFC stimulation. Kyn did not affect NAS CCK or Glu levels when perfused into either the VTA or NAS. The present results are consistent with histochemical evidence and provide the first in vivo evidence for the existence of a releasable pool of CCK in the NAS originating from the mPFC. Although dopamine is the transmitter most closely linked to reward function, it was CCK that showed frequency-dependent differences in release corresponding most closely to rewarding efficacy of the stimulation. Although not essential for the reward signal itself, coreleased CCK may modulate the impact of the glutamatergic action in this behavior." [Full Text]

Wu T, Wang HL.
CCK-8 excites substantia nigra dopaminergic neurons by increasing a cationic conductance.
Neurosci Lett 1994 Apr 11;170(2):229-32
"Using the whole-cell patch-clamp technique, we investigated electrophysiological effects of cholecystokinin on acutely isolated dopaminergic (DA) neurons of rat substantia nigra (SN). During voltage-clamp recordings, sulfated cholecystokinin octapeptide (CCK-8) dose-dependently induced an inward current at the holding potential of -7O mV. Under current-clamp recordings, CCK-8 depolarized DA neurons and triggered action potentials. CCK-8-evoked inward current reversed its direction at 1.0 +/- 1.9 mV (n = 9), and the amplitude of inward current induced by CCK-8 was reduced in an external solution with low sodium concentration. Cholecystokinin tetrapeptide (CCK-4), a selective CCK-B receptor agonist, failed to induce an inward current. CCK-8-evoked cationic current was antagonized by lorglumide, a selective CCK-A receptor antagonist. PD135, 158, a highly selective and potent CCK-B receptor antagonist, failed to attenuate CCK-8-induced cationic currents. These results suggest that by activating CCK-A receptors, CCK-8 excites SN DA neurons via increasing a non-selective cationic conductance." [Abstract]

GL Snyder, G Fisone, P Morino, V Gundersen, OP Ottersen, T Hokfelt, and P Greengard
Regulation by the Neuropeptide Cholecystokinin (CCK-8S) of Protein Phosphorylation in the Neostriatum
PNAS 90: 11277-11281, 1993.
"Despite physiological evidence that cholecystokinin (CCK) is an excitatory neurotransmitter in the brain, little is known about its mechanism of action. CCK immunoreactivity in the brain, including projections to the striatum, is primarily attributable to the sulfated octapeptide CCK-8S. We report here that CCK-8S abolishes cAMP-dependent phosphorylation of a dopamine- and cAMP-regulated 32-kDa phosphoprotein (DARPP-32) in striatal neurons. The effect of CCK-8S is prevented by antagonists of CCKB and N-methyl-D-aspartate receptors. Our results support a mod el in which CCK-8S, originating from CCK or CCK/glutamate corticostriatal neurons, promotes the release of an excitatory neurotransmitter that causes the dephosphorylation and inactivation of DARPP-32, a potent protein phosphatase inhibitor, thereby modulating neuronal excitability." [Abstract/Full Text]

Geracioti TD Jr, Ekhator NN, Nicholson WE, Arndt S, Loosen PT, Orth DN.
Intra- and inter-individual correlations between cholecystokinin and corticotropin-releasing hormone concentrations in human cerebrospinal fluid.
Depress Anxiety 1999;10(2):77-80
"Despite strong evidence of a physiologic relationship between cholecystokinin (CCK) and corticotropin-releasing hormone (CRH) in the rat central nervous system (CNS), evidence of such a relationship between the two hormones in the human CNS is lacking. A post hoc analysis of serial concentrations of immunoreactive CCK and CRH, obtained every ten minutes from CSF continuously collected over six hours, was performed. A total of 30 subjects were studied: 15 normal volunteers, 10 patients with major depression, and 5 recently-abstinent, alcohol-dependent patients. Overall, we observed an average intra-subject correlation of +.273 (P < 0.001) between CSF CRH and CCK. Inter-subject correlations between mean CSF levels of CRH and CCK were +.948 (P = 0.0001) and +.959 (P = 0.005) in the depressed and abstinent alcoholic patients, respectively. These inter-individual correlations were significantly greater than that seen within the group of normal volunteers (r = +.318, n.s.). The present data suggest that interactions between CCK and CRH are significant in the human CNS, particularly perhaps in depressed and alcoholic patients, and that CSF samples may be used to assess elements of the relationship between these hormones." [Abstract]

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