| 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.
Adrenaline and noradrenaline.
IN THE G PROTEIN-LINKED RECEPTOR FACTSBOOK, ACADEMIC PRESS, pp32-54.
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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].
In the periphery, the adrenergic system plays an important role in
regulating the cardiovascular system [6]. Increased sympathetic discharge
to the heart increases the rate and force of contraction mediated through
beta-1 receptors. Circulating adrenaline also acts on cardiac tissue, and,
in addition acts both on alpha-1 adrenoceptors in arterial smooth muscle,
stimulating vasoconstriction, and on beta-2 adrenoceptors in vascular beds
of skeletal muscle, stimulating vasodilation [6]. In the CNS, noradrenaline
is thought to be involved in the regulation of mood, and various psycho-
active drugs alter noradrenergic function. Numerous drugs exert their
actions via adrenoceptors: e.g., beta-2 selective agonists such as
salbutamol are used in the acute treatment of asthma, while alpha agonists
prolong the action of local anaesthetics, and act as nasal decongestants [6].
Adrenoceptors can be divided into three main classes based on sequence
similarity, receptor pharmacology and signalling mechanisms. Further
subdivisions exist within each class [6]. A large number of agonists and
antagonists distinguish between the different classes of adrenoceptor; by
contrast, relatively small differences in agonist and antagonist affinities
are demonstrated, especially within the alpha-1 and alpha-2 adrenoceptor
subtypes [6].
Beta-1 and beta-2 receptors often coexist, but one subtype normally
predominates [6]. Beta-1 receptors are the predominant subtype in cardiac
tissue (where they mediate positive inotropic and chronotropic effects) and
in the kidney (where they enhance renin release) [6]. The receptor activates
adenylyl cyclase through Gs [6].
ADRENRGCB1AR is a 7-element fingerprint that provides a signature for the
beta-1 adrenergic receptors. The fingerprint was derived from an initial
alignment of 5 sequences: the motifs were drawn from conserved sections
within either loop or N- and C-terminal regions, focusing on those areas
of the alignment that characterise the beta-1 adrenergic receptors but
distinguish them from the rest of the rhodopsin-like superfamily - motifs
1 and 2 span the N-terminus; motifs 3 and 4 lie in the third cytoplasmic
loop; motif 5 spans the third external loop; and motifs 6 and 7 lie at the
C-terminus. A single iteration on OWL28.1 was required to reach convergence,
no further sequences being identified beyond the starting set. Three partial
matches were also found: SSU56425 and S40503 are both beta-1 adrenergic
receptor fragments; and B1AR_MELGA is the turkey beta-T adrenergic receptor
whose sequence differs markedly from those of the rest of the beta-1
receptor family.
An update on SPTR37_9f identified a true set of 6 sequences, and 1
partial match.
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