| Literature References | 1. WANG, Z.Y., INGEGURD, K., OLSON, E.B.JNR., VIDRUK, E.H. AND BISGARD, G.E.
Expression of 5-HT3 receptors in primary sensory neurons of the petrosal
ganglion of adult rats.
AUTON.NEUROSCI. 95 121-124 (2002).
2. LEITE, J.F. AND CASCIO, M.
Structure of ligand-gated ion channels: critical assessment of biochemical
data supports novel topology.
MOL.CELL.NEUROSCI. 17(5) 777-792 (2001).
3. YAN, D., SCHULTE, M.K., BLOOM, K.E. AND WHITE M.M.
Structural features of the ligand-binding domain of the serotonin 5HT3
receptor.
J.BIOL.CHEM. 274 5537-5541 (1999).
4. DAVIES, P.A., PISTIS, M., HANNA, M.C., PETERS, J.A., LAMBERT, J.J., HALES,
T.G. AND KIRKNESS, E.F.
The 5-HT3B subunit is a major determinant of serotonin-receptor function.
NATURE 397 359-363 (1999).
5. DANG, H., ENGLAND, P.M., FARIVAR, S.S., DOUGHERTY, D.A. AND LESTER, H.A.
Probing the role of a conserved M1 proline residue in 5-hydroxytryptamine 3
receptor gating.
MOL.PHARMACOL. 57 1114-1122 (2000).
6. LOVINGER, D.
5-HT3 receptors and the neural actions of alcohols: an increasingly exciting
topic.
NEUROCHEM.INT. 35 125-130 (1999).
7. MARICQ, A.V., PETERSON, A.S., BRAKE, A.J., MYERS, R.M. AND JULIUS, D.
Primary structure and functional expression of the 5HT3 receptor, a
serotonin-gated ion channel.
SCIENCE 254 432-437 (1991).
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| Documentation | Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in both the
central and peripheral nervous system, where it acts as a neurotransmitter
and neuromodulator [1]. It has been implicated in several aspects of brain
function, including regulation of affective states, ingestive behavior and
addiction. 5-HT can activate a number of different receptor subtypes that
produce diverse neuronal responses, principally through activation of
G-protein-mediated signalling pathways. Signalling through the 5-HT3
receptor (5-HT3R) differs, since this subtype belongs to the ligand-gated
ion channel (LGIC) superfamily, which also includes the inhibitory
gamma-aminobutyric acid type A and glycine receptors, and excitatory
nicotinic acetylcholine receptors (nAChR) [2]. 5-HT3 receptor function has
been implicated in a variety of neural processes, including pain perception,
emesis, anxiety and drug abuse.
Like the other members of the LGIC superfamily, the 5HT3R exhibits a high
degree of sequence similarity, and therefore putative structural similarity,
with nAChRs [3]. Thus, funtional 5HT3Rs comprise a pentamer: the ion channel
is formed at the centre of a rosette formed between five homologous
subunits. Two classes of 5-HT3R subunit are currently known, termed 5-HT3A
and 5-HT3B. The proposed topology of 5-HT3R subunits comprises four putative
transmembrane (TM) domains (designated M1-4); a large extracellular
N-terminal region (~200 amino acids); and a variable cytoplasmic loop
between M3 and M4. The M2 domains from each subunit are thought to form the
channel pore [5]. The agonist binding site is formed by the N-terminus,
which, on binding, induces a conformational change in the channel pore, a
process often referred to as "gating" [5]. Opening of the pore allows cation
flux through the neuronal membrane and depolarises the membrane potential.
Thus, 5-HT3Rs may be thought of as excitatory receptors [6].
Cloning of the 5-HT3A subunit from a neuroblastoma expression library was
reported in 1991 [7]. Whilst recombinant expression of 5-HT3A yields
functional receptors, the channel conductance and permeability to cations
are different from that observed for native receptors [4]. Alternative exon
splicing gives rise to two isoforms of 5-HT3A, termed 5-HT3AS and 5-HT3AL
for short and long variants, respectively. The 5-HT3RA subunit is widely
expressed throughout the peripheral and central nervous systems, including
several regions of the brain.
5HT3ARECEPTR is a 5-element fingerprint that provides a signature for 5-HT3A
receptor subunits. The fingerprint was derived from an initial alignment of
3 sequences: the motifs were drawn from conserved regions spanning virtually
the full alignment length, focusing on those sections that characterise the
5-HT3A receptor subunits but distinguish them from 5-HT3B receptors - motifs
1 and 2 reside within the N-terminal domain; motifs 3 and 4 lie in the
variable cytoplasmic loop between M3 and M4; and motif 5 spans the
C-terminal portion of M4. Two iterations on SPTR40_20f were required to
reach convergence, at which point a true set comprising 10 sequences was
identified. A single partial match was also found, a putative truncated
human 5-HT3A subunit lacking the N-terminus and TM domain M1.
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