<p>G-protein-coupled receptors, GPCRs, constitute a vast protein family that encompasses a wide range of functions (including various autocrine, paracrine 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 [<cite idref="PUB00004961"/>]. 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. There is a specialised database for GPCRs (http://www.gpcr.org/7tm/). </p><p>The secretin-like GPCRs include secretin [<cite idref="PUB00001208"/>], calcitonin [<cite idref="PUB00005147"/>], parathyroid hormone/parathyroid hormone-related peptides [<cite idref="PUB00005148"/>] and vasoactive intestinal peptide [<cite idref="PUB00004310"/>], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N terminus is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allow the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. </p>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 [<cite idref="PUB00008074"/>]. 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 [<cite idref="PUB00008074"/>]. 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 [<cite idref="PUB00008075"/>]. 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 [<cite idref="PUB00008075"/>]. <p> 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 [<cite idref="PUB00008076"/>,<cite idref="PUB00008077"/>]. In humans, GLP-I exerts its physiological effect as an incretin. Patients with insulinoma tumors show uncontrolled insulin hypersecretion [<cite idref="PUB00008076"/>]. The GLP-I receptor binds GLP-1 with high affinity and couples to activation of adenylate cyclase [<cite idref="PUB00008078"/>]. The receptor specifically binds GLP-1 and not peptides of related structure and function, such as glucagon, gastric inhibitory peptide, VIP or secretin [<cite idref="PUB00008078"/>]. 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 [<cite idref="PUB00008077"/>]. </p> GPCR, family 2, glucagon-like peptide-1/glucagon receptor