Drug Targets CNS Neurol Disord. 2004 Feb;3(1):53-8.
"The 5-HT(5) receptor
family consists of two members designated as 5-HT(5A) and 5-HT(5B). To date the
5-HT(5A) receptor has been identified in the mouse, rat, and human. The 5-HT(5B)
receptor also is expressed in the mouse and rat, but not in the human where the
coding sequence is interrupted by stop codons. Both receptors are essentially
limited in distribution to the central nervous system (CNS), although the 5-HT(5A)
receptor has also been found on neurons and neuronal-like cells of the carotid
body. Within the CNS the 5-HT(5A) receptor shows a relatively broad distribution,
while the 5-HT(5B) receptor has a very restricted distribution. The 5-HT(5A) receptor
has been demonstrated to couple to G proteins, and the primary coupling appears
to be through Gi/o to inhibit adenylyl cyclase activity. The 5-HT(5) receptors
have not been extensively characterized pharmacologically. Both receptors show
their highest affinity for LSD, which appears to act as a partial agonist at the
5-HT(5A) receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine)
also has high affinity and has greater potency and affinity at the 5-HT(5A) receptor
than does 5-HT itself. Both [(125)I]LSD and [(5)H]5-CT have been used as radioligands
to study the receptors in vitro. Nothing is known about the role of the 5-HT(5B)
receptor in vivo. A mouse line has been developed where the 5-HT(5A) receptor
has been knocked out and these animals have been shown to have a diminished response
to LSD-induced increases in locomotion. The 5-HT(5) receptors remain as two of
the least studied and understood of the 5-HT receptor subtypes." [Abstract]
Grailhe, Gregg W. Grabtree, Rene Hen
Human 5-HT5 receptors: the 5-HT5A
receptor is functional but the 5-HT5B receptor was lost during mammalian evolution
Journal of Pharmacology 418 2001 157167
We have isolated from a human
genomic library the human 5-hydroxytryptamine 5-HT5A and 5-HT5B genes. The human
5-HT5A gene encodes a protein with similar characteristics to its mouse homologue.
When expressed in monkey COS-7 cells, the human 5-HT5A receptor displayed a high
affinity for tritiated 5-carbamidotryptamine ([3H]5-CT; Kd = 2.8 nM) and iodinated
lysergic acid diethylamide ([125I])LSD; Kd = 187 pM) . These binding sites displayed
the following displacement profile: Ergotamine > Methiothepin > 5-CT, Ritanserin
> 5-HT. Reverse transcriptase polymerase chain reaction RT-PCR experiments
revealed the presence of human 5-HT5A mRNA in the central nervous system but not
in peripheral organs. When expressed in Xenopus oocytes, the 5-HT5A receptor
was able to couple to the inwardly rectifying K+ channel, GIRK1. In contrast to
the human 5-HT5A gene and the mouse 5-HT5B gene, the human 5-HT5B gene does not
encode a functional protein because its coding sequence is interrupted by stop
codons. Our results suggest, therefore, that the 5-HT5B receptor has been lost
during evolution after the divergence between rodents and primates. The 5-HT5B
receptor is the first example of a brain-specific protein that is absent in human.
Grailhe R, Waeber C,
Dulawa SC, Hornung JP, Zhuang X, Brunner D, Geyer MA, Hen R.
exploratory activity and altered response to LSD in mice lacking the 5-HT(5A)
Neuron 1999 Mar;22(3):581-91
to determine the distribution and function of the 5-HT5A serotonin receptor subtype,
we generated knockout mice lacking the 5-HT5A gene. Comparative autoradiography
studies of brains of wild-type (wt) and 5-HT5A knockout (5A-KO) mice revealed
the existence of binding sites with high affinity for [125I]LSD that correspond
to 5-HT5A receptors and that are concentrated in the olfactory bulb, neocortex,
and medial habenula. When exposed to novel environments, the 5A-KO mice displayed
increased exploratory activity but no change in anxiety-related behaviors. In
addition, the stimulatory effect of LSD on exploratory activity was attenuated
in 5A-KO mice. These results suggest that 5-HT5A receptors modulate the activity
of neural circuits involved specifically in exploratory behavior and suggest that
some of the psychotropic effects of LSD may be mediated by 5-HT5A receptors."
M, Ori M, Nardi I, Castagna M, Cassano GB, Marazziti D.
of the 5-HT5A serotonin receptor mRNA in the human brain.
Brain Res Mol Brain Res 1998 May;56(1-2):1-8
"The 5-HT5A receptor is
a member of a new subfamily of serotonin [5-hydroxytryptamine (5-HT)] receptors
recently cloned from the human and rodent brain. The role of this receptor in
normal brain functions as well as its possible involvement in pathological states
is still to be determined. We therefore studied the regional distribution and
cellular localization of 5-HT5A receptor mRNA in human brain sections from autopsy
samples by in situ hybridization histochemistry, in order to obtain anatomical
information which might be useful in formulating hypotheses on possible functions
subserved by this receptor in the central nervous system (CNS). Our results showed
that the main sites of 5-HT5A mRNA expression were the cerebral cortex, hippocampus
and cerebellum. In the neocortical regions, the 5-HT5A receptor mRNA was mainly
distributed in the layers II-III and V-VI. In the hippocampus, the dentate gyrus
and the pyramidal cell layer of the CA1 and CA3 fields expressed 5-HT5A mRNA at
high levels. The broad distribution in the neocortex and hippocampus supports
the view that the 5-HT5A receptor in these areas might be implicated in high cortical
and limbic functions. The 5-HT5A mRNA was widely distributed in the cerebellum
where it was highly expressed in the Purkinje cells, in the dentate nucleus and,
at a lower level, in the granule cells. Since the cerebellum receives diffuse
serotonergic afferents, this finding suggests that the 5-HT5A receptor may have
an important role in mediating the effects of 5-HT on cerebellar functions. Copyright
1998 Elsevier Science B.V." [Abstract]
MJ, Thomas EA, Danielson PE, Sutcliffe JG.
The 5HT5A serotonin receptor
is expressed predominantly by astrocytes in which it inhibits cAMP accumulation:
a mechanism for neuronal suppression of reactive astrocytes.
Glia 1996 Aug;17(4):317-26
"The mRNA for the 5-hydroxytryptamine receptor
5-HT5A was detected at embryonic day 18 in the rat central nervous system and
peaked by postnatal day 20. At all time points examined, 5-HT5A immunoreactivity
observed on astrocyte cell bodies and in the stellate processes not only colocalized
with the astrocyte-specific marker glial fibrillary acidic protein (GFAP) but
was coordinately regulated with GFAP, increasing during development and during
gliosis. Transfection of 5-HT5A into glioma cells prevented the 5-HT-induced increase
in cAMP observed in untransfected cells and decreased the relative forskolin response
by approximately 20%, suggesting that the 5-HT5A receptor couples negatively to
adenylyl cyclase in astrocytes. Together, these results indicate a neuron-to-astrocyte
serotonergic signaling pathway mediating cAMP concentrations, which could provide
a neuronally driven mechanism for regulating astrocyte physiology with relevance
to gliosis." [Abstract]
ZY, Keith IM, Beckman MJ, Brownfield MS, Vidruk EH, Bisgard GE.
receptors in the carotid body chemoreception pathway of rat.
Neurosci Lett 2000 Jan 7;278(1-2):9-12
"By using a specific antibody,
5-HT5a receptor-like immunoreactivity was revealed in the chemoreceptive, oxygen
sensitive, carotid body (CB) type I cells, and neurons of the petrosal ganglion
(PG) and the superior cervical ganglion (SCG) in rat. mRNA encoding for the 5-HTa
receptor was also detected in these tissues by RT-PCR, and confirmed with DNA
sequencing. The present study provides direct evidence that 5-HT5a receptors are
expressed in the CB, PG and SCG, which all likely play fundamental roles in arterial
MG Erlander, TW Lovenberg, BM Baron, L de Lecea, PE Danielson,
M Racke, AL Slone, BW Siegel, PE Foye, K Cannon, JE Burns, and JG Sutcliffe
Two Members of a Distinct Subfamily of 5-Hydroxytryptamine Receptors
Differentially Expressed in Rat Brain
PNAS 90: 3452-3456,
Rees S, den Daas I,
Foord S, Goodson S, Bull D, Kilpatrick G, Lee M.
Cloning and characterisation
of the human 5-HT5A serotonin receptor.
FEBS Lett 1994
"The human 5-HT5A serotonin receptor has been cloned.
As with the mouse and rat 5-HT5A receptors, the gene consists of two coding exons
separated by a large intron. The deduced amino acid sequence of the gene reveals
a protein of 357 residues which shares 93% (nucleotide) and 84% (amino acid) identity
to the cloned mouse 5-HT5A receptor. We have determined the tissue distribution
of the receptor by reverse transcriptase-PCR and found expression in all regions
of the brain examined with little or no expression in peripheral tissues. The
receptor has been transiently expressed in Cos M6 cells and exhibits a pharmacological
profile closely resembling the mouse and rat 5-HT5A receptors with high, specific
binding for ergotamine and methiothepin." [Abstract]
C, Hanoun N, Ades J, Hamon M, Gorwood P.
studies between 5-HT5A receptor gene and schizophrenia.
Psychiatr Res. 2004 Jul-Aug;38(4):371-6.
and neurodevelopmental data support the idea that the gene, which codes for the
5-HT(5A) receptor is an important candidate gene for schizophrenia susceptibility.
However, previous genetic studies focusing on this gene yielded conflicting results,
potentially because of: (i) stratification biases of case-control association
studies, (ii) genetic and phenotypic heterogeneity of schizophrenia, and (iii)
variability in the loci analyzed (the 5-HT(5A) gene having many polymorphic sites).
METHODS: A transmission disequilibrium test was used in the present study aimed
at investigating two polymorphisms in exon 1 of the 5-HT(5A) gene, the A12T silent
substitution and the C43T transversion leading to a 15Pro --> Ser substitution,
in 103 patients with DSM-IV diagnosis of schizophrenia, and their 206 parents.
RESULTS: We found an excess of transmission of the 12T allele from the parents
to their affected children (P = 0.02), with evidence for linkage disequilibrium
between the 12T-43C haplotype and schizophrenia (P = 0.002). Furthermore, patients
with the 12T allele had a significantly later age at onset (P = 0.003), and the
Q-TDT approach confirmed that this allele was transmitted with an older age at
onset (P = 0.01). CONCLUSIONS: These data provided convergent evidence for a significant
role of the 5-HT(5A) gene in schizophrenia and more specifically in patients with
later age at onset." [Abstract]
Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin
RW, Collier DA.
Association analysis of the 5-HT5A gene in depression,
psychosis and antipsychotic response.
"The serotonergic system is targeted by both antidepressants
and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A
gene might be involved in susceptibility to depression, the major psychoses or
in influencing clinical response to treatment. To examine this hypothesis we genotyped
two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample
of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients,
75 unipolar patients and 187 controls. After five-fold correction for multiple
testing, allelic association was found with the -19G/C polymorphism and bipolar
affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52)
and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect
of the G19 allele. For the 12A/T polymorphism allelic association was observed
with unipolar depression only (p = 0.004). We conclude that allelic variation
in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia
and affective disorders but not in determining response to clozapine." [Abstract]
B, Collier DA, Gasto C, Pintor L, Gutierrez B, Valles V, Fananas L.
variation in the 5-HT5A receptor gene in patients with bipolar disorder and major
Neurosci Lett 2001 May 4;303(2):111-4
results suggest that the polymorphisms analyzed in the 5-HT5A receptor gene do
not play a major role in the pathogenesis of affective disorders." [Abstract]
Shimron-Abarbanell D, Erdmann J, Vogt IR, Bryant
SP, Spurr NK, Knapp M, Propping P, Nothen MM.
Human 5-HT5A receptor
gene: systematic screening for DNA sequence variation and linkage mapping on chromosome
7q34-q36 using a polymorphism in the 5' untranslated region.
Biochem Biophys Res Commun 1997 Apr 7;233(1):6-9
5-HT) is a neurotransmitter that mediates a wide range of sensory, motor, and
cortical functions by activating multiple 5-HT receptor subtypes. In the present
study we performed a systematic mutation scan of the complete coding region of
the 5-HT5A receptor to explore its variability in the general population. Investigating
46 unrelated healthy subjects by single-strand conformation analysis no sequence
changes of likely functional relevance were observed. The detection of a frequent
G-->C substitution at position -19 was used for fine scale linkage mapping
of the 5-HT5A gene. Employing a polymerase-chain-reaction based assay we genotyped
7 CEPH families (Centre d'Etude du Polymorphisme Humaine) and mapped the receptor
to genetic markers on chromosome 7q34-q36." [Abstract]
Francken, Bart J. B., Josson, Katty, Lijnen, Peter,
Jurzak, Mirek, Luyten, Walter H. M. L., Leysen, Josee E.
5-Hydroxytryptamine5A Receptors Activate Coexpressed Gi and Go Proteins in Spodoptera
frugiperda 9 Cells
Mol Pharmacol 2000 57: 1034-1044
"In summary, the h5-HT5A receptor selectively coupled to mammalian Gi1/Gi2/Gi3
and Go but not to Gz/Gs/Gq/11/16 or G12/13 proteins, when coexpressed in Sf9 insect
cells. Although Go displayed different receptor coupling characteristics than
Gi proteins, no clear coupling preference was evident." [Full
Francken BJ, Jurzak M, Vanhauwe JF, Luyten
WH, Leysen JE.
The human 5-ht5A receptor couples to Gi/Go proteins
and inhibits adenylate cyclase in HEK 293 cells.
Pharmacol 1998 Nov 20;361(2-3):299-309 [Abstract]
PT, McMahon, RA, Fanning, P, O'Boyle, KM, Rogers, M, Martin, F
coupling of a recombinant human 5-HT5A receptor to G- proteins in HEK-293 cells
Br. J. Pharmacol. 1998 124: 1238-1244 [Abstract/Full
Noda M, Yasuda S, Okada M, Higashida H,
Shimada A, Iwata N, Ozaki N, Nishikawa K, Shirasawa S, Uchida M, Aoki S, Wada
Recombinant human serotonin 5A receptors stably expressed in C6
glioma cells couple to multiple signal transduction pathways.
Neurochem. 2003 Jan;84(2):222-32.
"Human serotonin 5A (5-HT5A) receptors
were stably expressed in undifferentiated C6 glioma. In 5-HT5A receptors-expressing
cells, accumulation of cAMP by forskolin was inhibited by 5-HT as reported previously.
Pertussis toxin-sensitive inhibition of ADP-ribosyl cyclase was also observed,
indicating a decrease of cyclic ADP ribose, a potential intracellular second messenger
mediating ryanodine-sensitive Ca2+ mobilization. On the other hand, 5-HT-induced
outward currents were observed using the patch-clamp technique in whole-cell configuration.
The 5-HT-induced outward current was observed in 84% of the patched 5-HT5A receptor-expressing
cells and was concentration-dependent. The 5-HT-induced current was inhibited
when intracellular K+ was replaced with Cs+ but was not significantly inhibited
by typical K+ channel blockers. The 5-HT-induced current was significantly attenuated
by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) in the patch
pipette. Depleting intracellular Ca2+ stores by application of caffeine or thapsigargin
also blocked the 5-HT-induced current. Blocking G protein, the inositol triphosphate
(IP3) receptor, or pretreatment with pertussis toxin, all inhibited the 5-HT-induced
current. IP3 showed a transient increase after application of 5-HT in 5-HT5A receptor-expressing
cells. It was concluded that in addition to the inhibition of cAMP accumulation
and ADP-ribosyl cyclase activity, 5-HT5A receptors regulate intracellular Ca2+
mobilization which is probably a result of the IP3-sensitive Ca2+ store. These
multiple signal transduction systems may induce complex changes in the serotonergic
system in brain function." [Abstract]
DR, Larminie CG, Lyons HR, Fosberry A, Hill MJ, Hayes PD.
and pharmacological characterisation of the guinea pig 5-ht5A receptor.
J Pharmacol. 2004 Jun 28;494(2-3):91-9.
"The guinea pig 5-hydroxytryptamine(5A)
(gp5-ht(5A)) receptor was cloned from guinea pig brain using degenerate polymerase
chain reaction (PCR) and shows 88%, 85% and 84% amino acid sequence identity versus
the human, rat and mouse 5-ht(5A) receptors, respectively. The receptor was transiently
expressed in human embryonic kidney (HEK) 293 cells. [(3)H]-Lysergic acid diethylamide
(LSD) bound saturably to gp5-ht(5A)/HEK293 membranes with a K(d) of 2.3+/-0.1
nM and B(max) of 15.7+/-3.4 pmol/mg protein. The receptor binding profile, determined
by competition with [(3)H]LSD, correlated well with that for the human 5-ht(5A)
receptor. 5-HT stimulated [(35)S]GTPgammaS binding to gp5-ht(5A)/HEK293 membranes
(pEC(50) 8.1+/-0.2), and the response was surmountably antagonised by methiothepin
and ritanserin, giving apparent pK(B) values of 8.0 and 7.2, respectively. The
5-HT response was absent using membranes prepared from gp5-ht(5A)/HEK293 cells
pretreated with pertussis toxin (PTX). These data suggest that the gp5-ht(5A)
receptor couples to G(i)-proteins in this expression system and shows a similar
pharmacological profile to that for the human 5-ht(5A) receptor." [Abstract]
Geurts FJ, De Schutter E, Timmermans JP.
Localization of 5-HT2A,
5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum.
J Chem Neuroanat 2002 Jun;24(1):65-74
"Although serotonin (5-hydroxytryptamine,
5-HT) is known to exert a modulatory action on cerebellar function, our current
knowledge of the nature of receptor subtypes mediating serotonergic activity in
this part of the brain remains fragmentary. In this study, we report the presence
and distribution of 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in
the rat cerebellum using immunofluorescence histochemistry. 5-HT3 immunoreactivity
was found in fibers sparsely distributed throughout the cerebellum. Most of them
were seen in the cerebellar cortex as fine varicose 5-HT3-positive axonal processes.
5-HT5A immunoreactivity, on the other hand, was observed in neuronal somata of
the cerebellar cortex and deep cerebellar nuclei. Based upon cell morphology and
the use of cell-specific markers, Purkinje cells, molecular layer interneurons
and Golgi cells were found to be 5-HT5A immunopositive." [Abstract]
C, Grailhe R, Yu XJ, Hen R, Moskowitz MA.
Putative 5-ht5 receptors:
localization in the mouse CNS and lack of effect in the inhibition of dural protein
Ann N Y Acad Sci 1998 Dec 15;861:85-90
"Putative 5-ht5 receptor binding sites were visualized by in vitro autoradiography
using [125I]LSD (in the presence of clozapine and spiperone) or [3H]5-carboxamidotryptamine
(in the presence 8-OH-DPAT, GR127935 and spiperone). Under these conditions, no
[3H]5-carboxamidotryptamine labeling was detected in the brain of mice lacking
the gene encoding the putative 5-ht5a receptor (knockout mice), whereas intermediate
densities of binding sites were seen in the olfactory bulb and neocortex of wild-type
mice. [125I]LSD labeled the same areas as [3H]5-carboxamidotryptamine in wild-type
mice. High densities of [125I]LSD binding sites were observed in the medial habenula
of wild type and knockout mice. 5-CT competed for [125I]LSD binding sites with
an affinity of 2 nM in the olfactory bulb and neocortex of wild-type mice and
an affinity of 30 nM in the habenula of knockout mice, suggesting that habenular
labeling might be accounted for by putative 5-ht5b receptors. In the presence
of 5'-guanylylimidodiphosphate, 5-CT displaced [125I]LSD from putative 5-ht5a
and 5-ht5b sites with a 6-times and 3-times lower affinity, respectively, suggesting
that both receptor subtypes are coupled to G proteins in brain. We also studied
the inhibitory effect of 5-CT on dural neurogenic inflammation in knockout mice.
In wild type mice, 3 ng/kg 5-CT inhibited dural protein extravasation by 60%.
A similar effect was observed in knockout mice, even in the presence of the 5-HT1B
receptor antagonist GR127935. These results suggest that the inhibitory effects
of 5-CT are not mediated by a site with the characteristics of the putative 5-ht5
Identification of one of the least well understood 5-HT receptors
(5-ht(5A)) in the spinal cord.
J Comp Neurol. 2004 Aug 30;476(4):313-315.
DL, Sillar KT.
Divergent actions of serotonin receptor activation
during fictive swimming in frog embryos.
J Comp Physiol
A Neuroethol Sens Neural Behav Physiol. 2004 May;190(5):391-402. Epub 2004 Feb
"We have investigated the pharmacology underlying locomotor system
responses to serotonin (5-HT) in embryos of the frog, Rana temporaria, to provide
a comparison to studies in embryos of its close relative, Xenopus laevis. Our
findings suggest that two divergent mechanisms underlie the modulation of locomotion
by 5-HT in Rana. Bath-applied 5-HT or 5-carboxamidotyptamine, a 5-HT(1,5A,7) receptor
agonist, can modulate fictive swimming in a dose-dependent manner, increasing
burst durations and cycle periods. However, activation of 5-HT(1,7) receptors
with R8-OHDPAT or 8-OHDPAT fails to mimic 5-HT, and in some cases exerts exactly
the opposite response; decreasing burst durations and cycle periods. Elevating
endogenous 5-HT levels by blocking re-uptake with clomipramine transiently increases
burst durations. The receptors involved in this endogenous response include 5-HT(1A)
receptors, as in Xenopus, but also 5-HT(7) receptors. However, like the 8-OHDPAT
enantiomers, prolonged re-uptake inhibition can result in a motor response in
the opposite direction to exogenous 5-HT. This effect is not reversed by 5-HT(1A)
and/or 5-HT(7) receptor antagonism, implicating 5-HT(1B/1D) receptors. Remarkably,
antagonism of these receptors using methiothepin unmasks a dose-dependent response
to clomipramine, reminiscent of exogenous 5-HT. Our data suggest that 5-HT(1A,7)
and 5-HT(1B/1D) receptors act as gain-setters of burst durations, whilst 5-HT(5A)
receptors are involved in the effects of bath-applied 5-HT on locomotion."
W, Parker EM, Mahle CD, Grisel DA, Nowak HP, Yocca FD, Felder CC, Seeburg PH,
Cloning and characterization of the rat 5-HT5B receptor.
Evidence that the 5-HT5B receptor couples to a G protein in mammalian cell membranes.
FEBS Lett 1993 Oct 25;333(1-2):25-31
"A gene encoding a novel G protein-coupled
5-hydroxytryptamine (5-HT) receptor, termed 5-HT5B, was cloned. The ligand binding
profile of this receptor is distinct from that of other cloned 5-HT receptors.
The 5-HT5B receptor couples to a G protein in COS1 cell membranes; however, activation
of the 5-HT5B receptor does not appear to alter either cAMP accumulation or phosphoinositide
turnover in a variety of fibroblast cell lines. In the rat brain, 5-HT5B gene
expression occurs predominantly in the medial habenulae and hippocampal CA1 cells
of the adult. Little expression is seen during embryonic development." [Abstract]