| Literature References | 1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994).
2. ATTWOOD, T.K. AND FINDLAY, J.B.C.
G protein-coupled receptor fingerprints.
7TM, VOLUME 2, EDS. G.VRIEND AND B.BYWATER (1993).
3. BIRNBAUMER, L.
G proteins in signal transduction.
ANNU.REV.PHARMACOL.TOXICOL. 30 675-705 (1990).
4. CASEY, P.J. AND GILMAN, A.G.
G protein involvement in receptor-effector coupling.
J.BIOL.CHEM. 263(6) 2577-2580 (1988).
5. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Design of a discriminating fingerprint for G protein-coupled receptors.
PROTEIN ENG. 6(2) 167-176 (1993).
6. WATSON, S. AND ARKINSTALL, S.
5-Hydroxytryptamine.
IN THE G PROTEIN-LINKED RECEPTOR FACTSBOOK, ACADEMIC PRESS, 1994, PP.159-180.
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| Documentation | G protein-coupled receptors (GPCRs) constitute a vast protein family that
encompasses a wide range of functions (including various autocrine, para-
crine and endocrine processes). They show considerable diversity at the
sequence level, on the basis of which they can be separated into distinct
groups. We use the term clan to describe the GPCRs, as they embrace a group
of families for which there are indications of evolutionary relationship,
but between which there is no statistically significant similarity in
sequence [1]. The currently known clan members include the rhodopsin-like
GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating
pheromone receptors, and the metabotropic glutamate receptor family.
The rhodopsin-like GPCRs themselves represent a widespread protein family
that includes hormone, neurotransmitter and light receptors, all of
which transduce extracellular signals through interaction with guanine
nucleotide-binding (G) proteins. Although their activating ligands vary
widely in structure and character, the amino acid sequences of the
receptors are very similar and are believed to adopt a common structural
framework comprising 7 transmembrane (TM) helices [3-5].
5-Hydroxytryptamine (or serotonin) is ubiquitous in plants and animals.
It is an important neurotransmitter and local hormone in the CNS and
instestine, and is implicated in a vast array of physiological and patho-
physiological pathways [6]. In the periphery, 5HT contracts a number of
smooth muscles, and induces endothelium-dependent vasodilation through
the formation of NO [6]. It is a mediator of peristalsis, and may be
involved in platelet aggregation and homeostasis. In the CNS, 5HT is
believed to be involved in a wide range of functions, including the
control of appetite, mood, anxiety, hallucinations, sleep, vomiting and
pain perception [6]. 5HT receptor ligands are of clinical use in the
treatment of depression, migraine and post-operative vomiting.
Numerous receptor subtypes have been classified according to their
antagonist susceptibilities and their affinities for 5HT. Five 5HT1
subtypes and at least three 5HT2 subtypes have now been identified, in
addition to subtypes 5HT3-7 [6]. All share a high degree of sequence
similarity, and have overlapping pharmacological specificities.
5HT1-like receptors were originally classified according to their nano-
molar affinity for 5HT, susceptibility to antagonism by methiothepin and/or
methysegide, resistance to antagonism by 5HT2 and 5HT3 antagonists, and
high affinity for the agonist 5-carboxamidotryptamine [6]. Five subtypes
of 5HT1-like receptors have now been identified - these do not fit all the
above criteria, and 5HT1C has been reclassified 5HT2C [6]. All are linked
to the inhibition of adenylyl cyclase, share a high degree of sequence
similarity, and have overlapping pharmacological specificities.
The 5HT1A receptor is found pre- and post-synaptically in neurons in the
CNS, and in the periphery [6]. It is also abundant in foetal lymphatic
tissue. Clinically, 5HT1A receptor ligands represent potential anxiolytic
and hypertensive agents [6]. Several potent and selective 5HT1A receptor
agonists have been described; there are no selective antagonists.
5HT1ARECEPTR is a 7-element fingerprint that provides a signature for the
5HT1A receptors. The fingerprint was derived from an initial alignment of
4 sequences: the motifs were drawn from conserved sections within either
loop or N-terminal regions, focusing on those areas of the alignment that
characterise the 5HT1A receptors but distinguish them from the rest of the
5HT family - motifs 1 and 2 lie at the N-terminus; motif 3 spans the second
external loop; and motifs 4-7 lie in the third cytoplasmic loop. A single
iteration on OWL28.0 was required to reach convergence, no further sequences
being identified beyond the starting set. Three partial matches were also
found, all of which are 5HT1A receptor fragments.
An update on SPTR37_9f identified a true set of 3 sequences, and 2
partial matches.
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