Consequences of splice variation on secretin family G protein-coupled receptor function

The Secretin family of G protein-coupled receptors are endocrine peptide hormone receptors that share a common genomic organisation and are the subject of a wide variety of alternative splicing. All G protein-coupled receptors contain a central 7 transmembrane domain responsible for transducing signals from the outside of the cell as well as extracellular amino and intracellular carboxyl termini. Members of the Secretin receptor family have a relatively large N-terminus and a variety of lines of evidence support a common mode of ligand binding and a common ligand binding fold. These receptors are best characterized as coupling to intracellular signaling pathways via G(alphas) and G(alphaq) but are also reported to couple to a multitude of other signaling pathways. The intracellular loops are implicated in regulating the interaction between the receptor and heterotrimeric G protein complexes. Alternative splicing of exons encoding both the extracellular N-terminal domain as well as the extracellular loops of some family members has been reported and as expected these splice variants display altered ligand affinity as well as differential activation by endogenous ligands. Various forms of alternative splicing have also been reported to alter intracellular loops 1 and 3 as well as the C-terminus and as one might expect these display differences in signaling bias toward downstream effectors. These diverse pharmacologies require that the physiological role of these splice variants be addressed but should provide unique opportunities for drug design and development.