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

Abstract

Abstract. The G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that have a broad distribution and can collectively recognize 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 vary 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.

Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine

“…Alternative splicing is commonly seen among G protein-coupled receptors (GPCRs) (10)(11)(12). However, the extensive alternative splicing of OPRM1 is quite unusual, creating 3 structurally distinct classes of splice variants that are conserved from rodent to human: (a) fulllength 7-transmembrane (7TM) C-terminal variants; (b) truncated 6TM variants that lack exon 1 and the first TM; and (c) truncated single TM variants containing the first TM (ref.…”

A “tail” of opioid receptor variants

“…This refers to the observation that agonists for GPCRs can preferentially mediate the induction of specific downstream signals. Perhaps the best-studied example of biased agonism is the distinction between stimulation of G protein-mediated signals and β-arrestin-mediated signaling downstream of GPCRs (13). In the case of opioid receptors, β-arrestin-mediated signaling is thought to mediate tolerance (8).…”

“…GPCRs, such as the MOR, are known to undergo alternative splicing (13). The concept that MOR splice variants could explain differential binding affinities and pharmacological and side-effect profiles of opioids in different brain regions was initially pioneered by Pasternak and colleagues (3,14).…”

Kanserde yeni bir hedef haline gelen çok yönlü Sox2 geni

“…İntronsuz genlerin en büyük grubunu sinyal iletimiyle ilgili proteinleri kodlayan genler oluşturur (11). Bunların yaklaşık yarısı kadarı G-proteine bağlı reseptör genleridir (12).…”