| 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.
Melanocortins.
IN THE G PROTEIN-LINKED RECEPTOR FACTSBOOK, ACADEMIC PRESS, 1994, PP.180-191.
7. GANTZ, I., KONDA, Y., TASHIRO, T., SHIMOTO, Y., MIWA, H., MUNZERT, G.,
WATSON, S.J., DELVALLE, J. AND YAMADA, T.
Molecular cloning of a novel melanocortin receptor.
J.BIOL.CHEM. 268 8246-8250 (1993).
8. DESARNAUD, F., LABBE, O., EGGERICKX, D., VASSART, G. AND PARMENTIER, M.
Molecular cloning, functional expression and pharmacological
characterization of a mouse melanocortin receptor gene.
BIOCHEM.J. 299 367-373 (1994).
9. ROSELLI-REHFUSS, L., MOUNTJOY, K.G., ROBBINS, L.S., MORTRUD, M.T.,
LOW, M.J., TATRO, J.B., ENTWISTLE, M.L., SIMERLY, R.B. AND CONE, R.D.
Identification of a receptor for gamma melanotropin and other proopio-
melanocortin peptides in the hypothalamus and limbic system.
PROC.NATL.ACAD.SCI.U.S.A. 90 8856-8860 (1993).
10. ALVARO, J.D., TATRO, J.B., QUILLAN, J.M., FOGLIANO, M., EISENHARD, M.,
LERNER, M.R., NESTLER, E.J. AND DUMAN, R.S.
Morphine down-regulates melanocortin-4 receptor expression in brain regions that
mediate opiate addiction.
MOL.PHARMACOL. 50 583-591 (1996).
11. MOUNTJOY, K.G., MORTRUD, M.T., LOW, M.J., SIMERLY, R.B. AND CONE, R.D.
Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and
autonomic control circuits in the brain.
MOL.ENDOCRINOL. 8 1298-1308 (1994).
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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].
Adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (MSH) and
beta-endorphin are peptide products of pituitary pro-opiomelanocortin.
ACTH regulates synthesis and release of glucocorticoids and aldosterone
in the adrenal cortex; it also has a trophic action on these cells [6].
ACTH and beta-endorphin are synthesised and released in response to
corticotrophin-releasing factor at times of stress (heat, cold, infections,
etc.) - their release leads to increased metabolism and analgesia res..
MSH has a trophic action on melanocytes, and regulates pigment production
in fish and amphibia [6]. The ACTH receptor is found in high levels in
the adrenal cortex - binding sites are present in lower levels in the
CNS. The MSH receptor is expressed in high levels in melanocytes,
melanomas and their derived cell lines [6]. Receptors are found in low
levels in the CNS. MSH regulates temperature control in the septal region
of the brain and releases prolactin from the pituitary.
A further gene, which encodes a melanocortin receptor that is functionally
distinct from the ACTH and MSH receptors, has also been characterised [7-11].
The protein contains ~300 amino acids, with calculated molecular mass of
~36 KDa, and potential N-linked glycosylation and phosphorylation sites
[8]. The melanocortin 4 receptor (MC4-R) is regulated by opiate
administration [10]. Rat MC4-R is 95% identical to human MC4-R, and the
potency of melanocortin peptides to stimulate cAMP production is similar in
these two species homologues [10]. Expression of MC4-R mRNA was found to be
enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all
of which are regions implicated in the behavioral effects of opiates
(and are regions in which MC1-, MC3- and MC5-R are expressed at low or
undetectable levels) [10]. MC4-R mRNA has been found in multiple sites in
virtually every brain region, including the cortex, thalamus, hypothalamus,
brainstem, and spinal cord [11]. Unlike the MC3-R, MC4-R mRNA is found in
both parvicellular and magnocellular neurons of the paraventricular nucleus
of the hypothalamus, suggesting a role in the central control of pituitary
function [11].
MELNOCORTN4R is a 5-element fingerprint that provides a signature for the
melanocortin 4 receptors. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved regions
spanning the full alignment length, focusing on those sections that
characterise the melanocortin 4 receptors but distinguish them from
the rest of the melanocortin receptor family - motifs 1 and 2 lie at the
N-terminus; motif 3 lies in the first external loop; motif 4 spans the third
cytoplasmic loop; and motif 5 lies at the C-terminus. A single iteration
on OWL27.1 was required to reach convergence, no further sequences being
identified beyond the starting set. A single partial match was found,
B57055, a rat melanocortin 4 receptor fragment that matches motifs 3 and 4.
An update on SPTR37_9f identified a true set of 3 sequences.
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