Alternative Splicing of G Protein–Coupled Receptors: Relevance to Pain Management  Folabomi A. Oladosu, BS, William Maixner, PhD, DDS, Andrea G. Nackley, PhD  Mayo Clinic Proceedings  Volume 90, Issue 8, Pages 1135-1151 (August 2015) DOI: 10.1016/j.mayocp.2015.06.010 Copyright © 2015 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 1 G protein–coupled receptor (GPCR) structure and function. A, G protein–coupled receptors are composed of 7-transmembrane domains (gray) interconnected by 3 intracellular (orange) and 3 extracellular (purple) loops. On the end of the first and last transmembranes are the N-terminus (blue) and C-terminus (red), respectively. As its name suggests, a GPCR is bound to a trimeric G protein composed of α and β/γ subunits. B, When a ligand (black circle) 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). Mayo Clinic Proceedings 2015 90, 1135-1151DOI: (10.1016/j.mayocp.2015.06.010) Copyright © 2015 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 2 Different types of alternative splicing. The most common type of alternative splicing in animals is exon skipping (A), in which a constitutive exon is spliced from the final messenger RNA (mRNA) transcript. Alternative 3′ (B) and 5′ (C) 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. Mayo Clinic Proceedings 2015 90, 1135-1151DOI: (10.1016/j.mayocp.2015.06.010) Copyright © 2015 Mayo Foundation for Medical Education and Research Terms and Conditions

Figure 3 Structural variations in G protein–coupled receptors (GPCRs) as a result of alternative splicing. Exons within the messenger RNA 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, 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 a unit of the GPCR, such as a transmembrane, thus yielding a truncated GPCR lacking the encoded section, such as a 6-transmembrane (6-TM) splice variant. Mayo Clinic Proceedings 2015 90, 1135-1151DOI: (10.1016/j.mayocp.2015.06.010) Copyright © 2015 Mayo Foundation for Medical Education and Research Terms and Conditions