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1.A.9.2.1
Serotonin (5-hydroxytryptamine)-activated cation-selective receptor/channel, 5-HT3R. Residues in TMS2 and the cytoplasmic loop linking TMSs 3 and 4 influence conductance, selectivity, gating and desensitization (Peters et al., 2010; McKinnon et al., 2011). Resveratrol enhances ion currents (Lee et al., 2011). Rings of charge within the extracellular vestibule influence ion permeation (Livesey et al., 2011).  Based on the 3-d structure, serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway (Yuan et al. 2016). There are 5 isoforms of 5-HT3A which include 5-HT3AB, 5-HT3AC, 5-HT3AD, and 5-HT3AE, all of which have similar but distinct pharmacological profiles compared to those of 5-HT3A receptors (Price et al. 2017). Trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA) is a potent agonist with behavior different from that of 5-HT (Gasiorek et al. 2016). Two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations   reveal the mechanism underlying channel activation (Basak et al. 2018). he trans-cis isomerization of a proline at the interface between the extracellular and transmembrane domain may be the switch between closed and open states of the channel (Crnjar et al. 2019).  SR 57227A is the most commonly used 5-HT3 receptor agonist with the ability to cross the blood brain barrier (Nakamura et al. 2019).

Accession Number:P46098
Protein Name:5HT3 aka HTR3 aka HTR3A aka 5HT3R
Length:478
Molecular Weight:55280.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell junction1 / Multi-pass membrane protein2
Substrate inorganic cations

Cross database links:

Genevestigator: P46098
RefSeq: NP_000860.2    NP_001155244.1    NP_998786.2   
Entrez Gene ID: 3359   
Pfam: PF02931    PF02932   
Drugbank: Drugbank Link   
OMIM: 182139  gene
KEGG: hsa:3359   

Gene Ontology

GO:0030054 C:cell junction
GO:0005887 C:integral to plasma membrane
GO:0045211 C:postsynaptic membrane
GO:0051378 F:serotonin binding
GO:0004993 F:serotonin receptor activity
GO:0005232 F:serotonin-activated cation-selective channe...
GO:0007586 P:digestion
GO:0006811 P:ion transport
GO:0007268 P:synaptic transmission

References (12)

[1] “Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species.”  Miyake A.et.al.   7565620
[2] “Cloning and functional expression of a human 5-hydroxytryptamine type 3AS receptor subunit.”  Belelli D.et.al.   8848005
[3] “Molecular cloning of alternatively spliced human 5HT3 receptor cDNAs.”  Bruess M.et.al.   9928262
[4] “Exon-intron organization of the human 5-HT3A receptor gene.”  Bruess M.et.al.   10670426
[5] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[6] “The 5-HT3B subunit is a major determinant of serotonin-receptor function.”  Davies P.A.et.al.   9950429
[7] “The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit.”  Dubin A.E.et.al.   10521471
[8] “A cytoplasmic region determines single-channel conductance in 5-HT3 receptors.”  Kelley S.P.et.al.   12867984
[9] “Cell surface expression of 5-hydroxytryptamine type 3 receptors is promoted by RIC-3.”  Cheng A.et.al.   15809299
[10] “Characterization of the novel human serotonin receptor subunits 5-HT3C, 5-HT3D, and 5-HT3E.”  Niesler B.et.al.   17392525
[11] “Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients.”  Frank B.et.al.   15293096
[12] “Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression.”  Yamada K.et.al.   16487942

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MLLWVQQALL ALLLPTLLAQ GEARRSRNTT RPALLRLSDY LLTNYRKGVR PVRDWRKPTT 
61:	VSIDVIVYAI LNVDEKNQVL TTYIWYRQYW TDEFLQWNPE DFDNITKLSI PTDSIWVPDI 
121:	LINEFVDVGK SPNIPYVYIR HQGEVQNYKP LQVVTACSLD IYNFPFDVQN CSLTFTSWLH 
181:	TIQDINISLW RLPEKVKSDR SVFMNQGEWE LLGVLPYFRE FSMESSNYYA EMKFYVVIRR 
241:	RPLFYVVSLL LPSIFLMVMD IVGFYLPPNS GERVSFKITL LLGYSVFLII VSDTLPATAI 
301:	GTPLIGVYFV VCMALLVISL AETIFIVRLV HKQDLQQPVP AWLRHLVLER IAWLLCLREQ 
361:	STSQRPPATS QATKTDDCSA MGNHCSHMGG PQDFEKSPRD RCSPPPPPRE ASLAVCGLLQ 
421:	ELSSIRQFLE KRDEIREVAR DWLRVGSVLD KLLFHIYLLA VLAYSITLVM LWSIWQYA