Alternative Splicing of G Protein-Coupled Receptors: Relevance to Pain Management

Abstract

Drugs that target G protein-coupled receptors (GPCRs) represent the primary treatment strategy for patients with acute and chronic pain; however, there is substantial individual variability in both the efficacy and adverse effects associated with these drugs. Variability in drug responses is due, in part, to individuals' diversity in alternative splicing of pain-relevant GPCRs. G protein-coupled receptor alternative splice variants often exhibit distinct tissue distribution patterns, drug-binding properties, and signaling characteristics that may impact disease pathology as well as the extent and direction of analgesic effects. We review the importance of GPCRs and their known splice variants to the management of pain.

Figure 1

GPCR structure and function. A) A g-protein coupled receptor (GPCR) is composed of seven transmembranes (grey) interconnected by three intracellular (orange) and three extracellular (purple) loops. On the end of the first and last transmembrane are the N-terminus (blue) and C-terminus (red), respectively. As its name suggests, a GPCR is bound to a tri-meric g-protein composed of alpha (α) and beta/gamma (β/γ) subunits. B) When a ligand (black) binds to a GPCR, the associated g-protein separates into the α and β/γ subunits. These subunits then stimulate a variety of downstream effectors that produce changes in cellular activity (see Table 1). Abbreviations: GPCR = G-Protein Coupled Receptor

Figure 2

Different types of alternative splicing. The most common type of alternative splicing in animals is A) exon skipping, in which a constitutive exon is spliced from the final mRNA transcript. Alternative B) 3’ and C) 5’ splice sites provide additional junctions within an exon, resulting in partial splicing of the exonic mRNA sequence. D) Intron retention is a rare type of alternative splicing that occurs when an intron remains within the final mRNA transcript. Abbreviations: mRNA = Messenger Ribonucleic Acid

Figure 3

Structural variations in GPCRs as a result of alternative splicing. Exons within the mRNA transcript serve as coding regions for specific sections of protein. Alternative splicing events that change or remove exonic sequences can produce GPCR splice variants with corresponding changes in protein composition and/or structure. A) For example, splicing events that lead to alterations in exon 1 can yield GPCRs with truncated N-termini that affect ligand binding, while events that lead to alterations in exon 4 can yield GPCRs with truncated C-termini that affect g-protein coupling and signaling. B) Splicing events can also lead to skipping of an exon that codes for an unit of the GPCR, such as a transmembrane, thus yielding a truncated GPCR lacking the encoded section, such as a 6 transmembrane (6TM) splice variant. Abbreviations: GPCR = G-Protein Coupled Receptor; TM = Transmembrane