| Literature References | 1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994).
2. ISHIHARA T., NAKAMURA S., KAZIRO, Y., TAKAHASHI, T., TAKAHASHI, K.
AND NAGATA, S.
Molecular cloning and expression of a cDNA encoding the secretin receptor
EMBO J. 10 1635-1641 (1991).
3. LIN, H.Y., HARRIS, T.L., FLANNERY, M.S., ARUFFO, A., KAJI, E.H.,
GORN, A., KOLAKOWSKI, L.F., LODISH, H.F. AND GOLDRING, S.R.
Expression cloning of adenylate cyclase-coupled calcitonin receptor
SCIENCE 254 1022-1024 (1991).
4. JUEPPNER, H., ABOU-SAMRA, A.-B., FREEMAN, M., KONG, X.F.,
SCHIPANI, E., RICHARDS, J., KOLALOWSKI, L.F., HOCK, J., POTTS, J.T.,
KRONENBERG, H.M. AND SEGRE, G.E.
A G protein linked receptor for parathyroid hormone and parathyroid
hormone-related peptide.
SCIENCE 254 1024-1026 (1991).
5. ISHIHARA, T., SHIGEMOTO, R., MORI, K., TAKAHASHI, K. AND NAGATA, S.
Functional expression and tissue distribution of a novel receptor for
vasoactive intestinal polypeptide.
NEURON 8(4) 811-819 (1992).
6. BURCELIN, R., LI, J. AND CHARRON, M.J.
Cloning and sequence analysis of the murine glucagon receptor-encoding gene.
GENE 164 305-310 (1995).
7. JELINEK, L.J., LOK, S., ROSENBERG, G.B., SMITH, R.A., GRANT, F.J.,
BIGGS, S., BENSCH, P.A., KUIJPER, J.L., SHEPPARD, P.O., SPRECHER, C.A.
Expression cloning and signaling properties of the rat glucagon receptor.
SCIENCE 259 1614-1616 (1993).
8. VAN EYLL, B., LANKAT-BUTTGEREIT, B., BODE, H.P., GOKE, R. AND GOKE, B.
Signal transduction of the GLP-1-receptor cloned from a human insulinoma.
FEBS LETT. 348 7-13 (1994).
9. WEI, Y. AND MOJSOV, S.
Tissue-specific expression of the human receptor for glucagon-like
peptide-I: brain, heart and pancreatic forms have the same deduced amino
acid sequences.
FEBS LETT. 358 219-224 (1995).
10. THORENS, B.
Expression cloning of the pancreatic beta cell receptor for the gluco-
incretin hormone glucagon-like peptide 1.
PROC.NATL.ACAD.SCI.U.S.A. 89 8641-8645 (1992).
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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 secretin-like GPCRs include secretin [2], calcitonin [3], parathyroid
hormone/parathyroid hormone-related peptides [4] and vasoactive intestinal
peptide [5], all of which activate adenylyl cyclase and the phosphatidyl-
inositol-calcium pathway. 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 inter-
act with G proteins. However, while a similar 3D framework has been
proposed to account for this, there is no significant sequence similarity
between these families: the secretin-like receptors thus bear their own
unique `7TM' signature.
The glucagon receptor (GR) plays a central role in regulating the level of
blood glucose by controlling the rate of hepatic glucose production and
insulin secretion [6]. GR is expressed predominantly in liver, kidney,
adrenal, lung and stomach, with lower levels of expression detected in
brown and white adipose tissue, cerebellum, duodenum and heart [6]. Their
role in the control of blood glucose concentrations makes glucagon and GR
especially important to studies of diabetes, in which the loss of control
over blood glucose concentrations clinically defines the disease [7]. GR is
similar to the secretin-like receptor superfamily. It can transduce signals
leading to the accumulation of two different second messengers - i.e., both
cAMP and calcium [7].
Glucagon-like peptide-1 (GLP-1), which is encoded by the glucagon gene and
released from the gut in response to nutrients, is a potent stimulator of
glucose-induced insulin secretion and proinsulin gene expression of
pancreatic beta-cells [8,9]. In humans, GLP-I exerts its physiological
effect as an incretin. Patients with insulinoma tumors show uncontrolled
insulin hypersecretion [8]. The GLP-I receptor binds GLP-1 with high
affinity and couples to activation of adenylate cyclase [10]. The receptor
specifically binds GLP-1 and not peptides of related structure and function,
such as glucagon, gastric inhibitory peptide, VIP or secretin [10]. It is
thought that GLP-I might have effects beyond the pancreas, including the
cardiovascular and central nervous systems, where a receptor with the same
ligand-binding specificity is found [9].
GLUCAGNFAMLY is a 4-element fingerprint that provides a signature for the
glucagon family of secretin-like GPCRs. The fingerprint was derived from an
initial alignment of 6 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length, focusing on those
sections that characterise the glucagon receptor family but distinguish
them from the rest of the secretin-like GPCR superfamily - motifs 1-3 span
the N-terminal putative extracellular domain; and motif 4 spans the third
extracellular loop. A single iteration on SPTR37_10f was required to reach
convergence, no further sequences being identified beyond the starting set.
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