Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function.

GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are G-coupled and lead to intracellular accumulation of inositol phosphates and calcium release.

The L-α-amino acid receptor GPRC6A is expressed in the islets of Langerhans but is not involved in L-arginine-induced insulin release.

GPRC6A is a seven-transmembrane receptor activated by a wide range of L-α-amino acids, most potently by L-arginine and other basic amino acids. The receptor is broadly expressed, but its exact physiological role remains to be elucidated. It is well established that L-arginine stimulates insulin secretion; therefore, the receptor has been hypothesized to have a role in regulating glucose metabolism.

The emerging role of promiscuous 7TM receptors as chemosensors for food intake.

In recent years, several highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized of which many are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids (FFAs) and are expressed in taste tissue, the gastrointestinal (GI) tract, endocrine glands, adipose tissue, and/or kidney. This has led to the hypothesis that these receptors may act as sensors of food intake modulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. In the present review, we describe the molecular mechanisms of nutrient-sensing of the calcium-sensing receptor (CaR), the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3-sensing L-α-amino acids; the carbohydrate-sensing T1R2/T1R3 receptor; the proteolytic degradation product sensor GPR93 (also termed GPR92); and the FFA sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120.

Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients.

A number of highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized within the last few years. It is noteworthy that many of these receptors are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids and are expressed in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue.

No evidence for a bone phenotype in GPRC6A knockout mice under normal physiological conditions.

GPRC6A is a seven-transmembrane receptor mediating signaling by a wide range of L-alpha-amino acids, a signaling augmented by the divalent cations Ca(2)(+) and Mg(2)(+). GPRC6A transcripts are detected in numerous mammalian tissues, but the physiological role of the receptor is thus far elusive. Analogously to the closely related calcium-sensing receptor, GPRC6A has been proposed to function as a metabolic sensor of Ca(2)(+) and amino acids in bone and other tissues.

IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration.

Loss-of-function mutations in the IKBKAP gene, which encodes IKAP (ELP1), cause familial dysautonomia (FD), with defective neuronal development and maintenance. Molecular mechanisms leading to FD are poorly understood. We demonstrate that various RNA-interference-based depletions of IKAP lead to defective adhesion and migration in several cell types, including rat primary neurons.