Abstract
G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application.
Highlights
Gprotein-coupled receptors (GPCRs) constitute the largest and most versatile superfamily of cell membrane-bound proteins, made up of seven trans-membrane α-helices (TM1 to TM7) [1–3] connected by intracellular (IL-1 to IL-3) and extracellular loops (EL-1 to EL-3), and coupled to an intracellular heterotrimeric G protein (e.g., Gs, Gi/o, Gq/11, G12/13) [4]
GPCRs are commonly grouped into six subfamilies (A-F) [5], based on sequence homology and functionality
Described as cell-surface monomers that form a ternary complex with the extracellular ligand and the intracellular G protein [14], GPCR higher-order oligomers have in recent years been increasingly recognized as novel signaling units with functional properties distinct from their constituent receptors
Summary
Gprotein-coupled receptors (GPCRs) constitute the largest and most versatile superfamily of cell membrane-bound proteins, made up of seven trans-membrane α-helices (TM1 to TM7) [1–3] connected by intracellular (IL-1 to IL-3) and extracellular loops (EL-1 to EL-3), and coupled to an intracellular heterotrimeric G protein (e.g., Gs, Gi/o, Gq/11, G12/13) [4]. GPCRs are commonly grouped into six subfamilies (A-F) [5], based on sequence homology and functionality Despite this apparent diversity, all GPCRs mediate their effects upon agonist-induced activation of the receptor at the extracellular site by a wide variety of ligands and transduce the signal into intracellular responses [6]. Described as cell-surface monomers that form a ternary complex with the extracellular ligand and the intracellular G protein [14], GPCR higher-order oligomers have in recent years been increasingly recognized as novel signaling units with functional properties distinct from their constituent receptors, . We consider the challenges and opportunities involved in disrupting GPCR oligomer formation by means of TM peptides targeting the complex interface, as a way to regulate oligomerization-dependent functions, and we discuss strategies reported to improve the druggability of such peptide candidates in the context of cannabinoid-mediated pain management or CNS disorders
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
