G Protein–Coupled Receptors—Receptors With New Tricks Up Their Sleeves

Abstract

G protein receptors (GPCRs) continue to fascinate and confound. Since 2012 when Brian Kobilka and Robert Lefkowitz received the Nobel Prize in Chemistry for their pioneering work on the beta-adrenergic receptor structure, GPCRs have been the subject of over 9250 articles appearing on PubMed. Approximately 13% of these deal with drug discovery or development. Overall, approximately 35% of all Food and Drug Administration approved small molecule drugs target GPCRs. 1 Yet many fundamental features of signaling by GPCR family members, including the dynamics and mechanisms that fine-tune their interactions with heterotrimeric G proteins and other binding partners and the functional consequences of various modes of GPCR activation, have only recently been exposed. [2][3][4] This issue of the Journal of Cardiovascular Pharmacology contains a special series entitled Cardiovascular Regulation by GPCRs organized by one of us (Susan Steinberg) that includes 7 outstanding invited review articles, each entry updating a different recent development pertaining to a novel aspect of GPCR biology.Wingler and Feld 5 discussed nanobodies as novel tools for both probing and regulating GPCR activation. Nanobodies are fashioned on the variable regions of camelid heavy chain only antibodies and are typically designed to "capture" a native GPCR in a specific conformation, either active or inactive. They discuss strategies for developing nanobodies targeted to specific surfaces of the GPCR, including nanobodies designed to act at intracellular transducer-binding or allosteric sites and nanobodies that recognize orthosteric or allosteric sites on the extracellular surface. They discuss how one might potentially use a nanobody approach as a strategy to achieve biased agonism and to activate the receptor in a manner that favors signaling through either G protein-dependent or b-arrestin-dependent