Isoform-specific GPCR Functions

a) Functional consequences of RNA editing of the 5HT_2C receptor

The 5-HT_2C family of GPCRs play an important role in the central nervous system and have been implicated in disorders such as schizophrenia, anxiety and depression. We are currently investigating potential mechanisms underlying ligand-mediated regulation of 5-HT_2C receptors, including the role of novel signalling pathways and accessory proteins. We have recently characterized the coupling of this receptor to the ERK1/2 MAP kinase pathway, and are currently investigating the effect of RNA editing of the 5HT2C receptor on its coupling to ERK. This is a post-transcriptional process whereby 5HT_2C receptor pre-RNA is modified to generate up to 24 potential isoforms that differ in a triplet of amino acids in the second intracellular loop of the receptor. Because this region is important in receptor-G protein coupling, RNA editing can generate receptor isoforms with markedly different signalling properties.

Polymorphic variants of the human calcitonin receptor

Many of the actions affecting nutritional status, including inhibition of food intake and inhibition of gastric emptying, occur via calcitonin receptors in the central nervous system. Recently a single nucleotide polymorphism (SNP) in the C-terminal intracellular domain of the calcitonin receptor was described, leading to either a proline or a leucine at the polymorphic site. In a population specific manner, presence of this polymorphism has been correlated with osteoporotic risk (bone mineral density), fracture risk, body weight and prevalence of kidney stones. There is also a marked ethnic bias in the distribution of alleles for each of the polymorphic variants with Asian populations having predominately proline homozygotes and Caucasians having high prevalence of leucine homozygotes and heterozygotes but low levels of proline homozygotes. We have been investigating the molecular consequences of this polymorphism. Our data indicate that distinct polymorphic variants interact differently with the two species of calcitonin that are most commonly used clinically; salmon calcitonin and human calcitonin, respectively. This data implies that it may be possible to tailor genotype-specific therapy to improve the clinical outcome of disease treatment with calcitonins.