Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Abstract

The G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that have a broad distribution and can collectively recognise a diverse array of ligands. Activation or inhibition of GPCR signalling can affect many (patho)physiological processes, and consequently they are a major target for existing and emerging drug therapies. A common observation has been that the pharmacological, signalling and regulatory properties of GPCRs can differ in a cell- and tissue-specific manner. Such "phenotypic" diversity might be attributable to post-translational modifications and/or association of GPCRs with accessory proteins, however, post-transcriptional mechanisms are also likely to contribute. Although approximately 50% of GPCR genes are intronless, those that possess introns can undergo alternative splicing, generating GPCR subtype isoforms that may differ in their pharmacological, signalling and regulatory properties. In this review we shall highlight recent research into GPCR splice variation and discuss the potential consequences this might have for GPCR function in health and disease.

Fig. 1

Overview of GPCRs encoded by more than one exon. In the “pre-human genome era” it was assumed that more than 90% of human GPCRs were intronless [15]. However, analysis from various databases and bioinformatic studies indicate that the number of intron-containing GPCRs has been under-estimated. Using a list of over 350 GPCRs from the IUPHAR database and examining their ORF sequences for the presence of alternate exons (using CCDS data from NCBI), it is obvious that a large number of GPCRs contain more than one exon (52%). This does not mean that all of them can be expressed as alternatively spliced variants (mRNA) or isoforms (proteins), but that they are not intronless. These data are also likely to be an under-estimate because if the CCDS data are not available for a gene, we would assign the GPCR as intronless

Fig. 2

Schematic representation of GPCR structure summarising potential splice variants. The 7TM domains are shown as blue cylinders; the N-terminus is facing the extracellular side of the plasma membrane, while the C-terminus is intracellular. The events that lead to translation of alternatively spliced isoforms are outlined in the boxes