| Literature References | 1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994).
2. MASU, M., TANABE, Y., TSUCHIDA, K., SHIGEMOTO, R. AND NAKANISHI, S.
Sequence and expression of a metabotropic glutamate receptor.
NATURE 349 760-765 (1991).
3. HOUAMED, K.M., KUIJPER, J.L., GILBERT, T.L., HALDEMAN, B.A., OHARA, P.J.,
MULVIHILL, E.R., ALMERS, W. AND HAGEN, F.S.
Cloning, expression and gene structure of a G protein-coupled glutamate
receptor from rat brain.
SCIENCE 252 1318-1321 (1991).
4. ABE, T., SUGIHARA, H., NAWA, H., SHIGEMOTO, R., MIZUNO, N. AND
NAKANISHI, S.
Molecular characterisation of a novel metabotropic glutamate receptor
MGLUR5 coupled to inositol phosphate/Ca2+ signal transduction.
J.BIOL.CHEM. 267(19) 13361-13368 (1992).
5. TANABE, Y., MASU, M., ISHII, T., SHIGEMOTO, R. AND NAKANISHI, S.
A family of metabotropic glutamate receptors.
NEURON 8(1) 169-179 (1992).
6. BROWN, E.M., GAMBA, G., RICCARDI, D., LOMBARDI, M., BUTTERS, R.,
KIFOR, O., SUN, A., HEDIGER, M.A., LYTTON, J. AND HEBERT, S.C.
Cloning an characterisation of an extracellular Ca(2+)-sensing receptor
from bovine parathyroid.
NATURE 366 575-580 (1993).
7. WARD, B.K., STUCKEY, B.G., GUTTERIDGE, D.H., LAING, N.G., PULLAN, P.T.
AND RATAJCZAK, T.
A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with
familial hypocalciuric hypercalcemia.
HUM.MUTAT. 10 233-235 (1997).
8. PEARCE, S.H., TRUMP, D., WOODING, C., BESSER, G.M., CHEW, S.L., GRANT, D.B.,
HEATH, D.A., HUGHES, I.A., PATERSON, C.R. AND WHYTE, M.P.
Calcium-sensing receptor mutations in familial benign hypercalcemia and
neonatal hyperparathyroidism.
J.CLIN.INVEST. 96 2683-2692 (1995).
9. POLLAK, M.R., BROWN, E.M., ESTEP, H.L., MCLAINE, P.N., KIFOR, O.,
PARK, J., HEBERT, S.C., SEIDMAN, C.E. AND SEIDMAN, J.G.
Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene
mutation.
NAT.GENET. 8 303-307 (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 metabotropic glutamate receptors are functionally and pharmacologically
distinct from the ionotropic glutamate receptors. They are coupled to G-
proteins and stimulate the inositol phosphate/Ca2+ intracellular signalling
pathway [2-5]. The amino acid sequences of the receptors contain high
proportions of hydrophobic residues grouped into 7 domains, in a manner
reminiscent of the rhodopsins and other receptors believed to interact with
G proteins. However, while a similar 3D framework has been proposed to
account for this, there is no significant sequence identity between these
and receptors of the rhodopsin-type family: the metabotropic glutamate
receptors thus bear their own distinctive `7TM' signature.
The calcium-sensing receptor (CaSR) is an integral membrane protein that
senses changes in the extracellular concentration of calcium ions. The
activity of the receptor is mediated by a G protein that activates a
phosphatidyl-inositol-calcium second messenger system. The sequences of the
receptors show a high degree of similarity to the TM signature that
characterises the metabotropic glutamate receptors. In addition, the
sequences contain a large extracellular domain that includes clusters of
acidic amino acid residues, which may be involved in calcium binding [6].
Defects in CaSR that result in reduced activity of the receptor cause
familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperpara-
thyroidism (NSHPT), inherited conditions characterised by altered calcium
homeostasis [7,8]. FHH-affected individuals exhibit mild or modest hyper-
calcemia, relative hypocalciuria and inappropriately normal PTH levels. By
contrast, NSHPT is a rare autosomal recessive life-threatening disorder
characterised by high serum calcium concentrations, skeletal demineral-
isation and parathyroid hyperplasia. In addition, defects resulting from
receptor activation at subnormal Ca(2+) levels cause autosomal dominant
hypocalcemia [9].
CASENSINGR is a 13-element fingerprint that provides a signature for the
calcium-sensing receptors. The fingerprint was derived from an initial
alignment of 6 sequences: the motifs were drawn from conserved regions
spanning the full alignment length, focusing on those sections that
characterise the calcium-sensing receptors but distinguish them from the
rest of the metabotropic receptor superfamily - motifs 1-11 lie in the
N-terminal extracellular domain; motif 12 resides in the second cytoplasmic
loop, between putative TM domains 3 and 4; and motif 13 lies in the
C-terminal cytoplasmic domain. A single iteration on OWL31.1 was required
to reach convergence, no further sequences being identified beyond the
starting set. Several partial matches were found, all of which are fragments
and calcium-sensing receptor homologues that match 2 motifs.
An update on SPTR37_9f identified a true set of 4 sequences, and 5
partial matches.
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