LAUSR

This Special Issue of Molecular and Cellular Endocrinology on ‘Pleiotropic G protein-coupled receptor (GPCR) signaling in health and disease’ illustrates the exquisite complexity of GPCR signal systems, current approaches to decode this complexity and progress in understanding the impact of these pleotropic systems to physiology, specifically endocrine functions, and in human disease. There are more than 800 different GPCRs in humans, playing central roles in almost all physiological systems. Furthermore, with >30% current drugs targeting these receptors, they represent a family of signaling molecules with paramount importance in understanding endocrine functions, from the molecular to clinical level. Over the past two decades our view of GPCR signaling has evolved from a simple linear system where an individual receptor at the plasmamembrane activates specific heterotrimeric G protein pathways, to one that is pluridimensional in its responses. Our molecular understanding of this superfamily of signaling receptors has been rapidly advanced by the generation of high resolution crystal structures of distinct active receptor states, including complexes with key protein partners, G proteins and the GPCR adaptor proteins the arrestins. These seminal studies led to the 2012 Nobel prize in Chemistry to Brian Kobilka and Robert Lefkowitz. The intricate details in ligand-receptor interactions and receptor activation states from these crystal structures has revolutionized drug targeting strategies to this highly desirable and successful super-group of therapeutic targets. The article by Woolley and Conner (2017) discuss advancements in our understanding of a key ligandbinding/activation domain of GPCRs emerged from recent structural information, that highlight the critical role for the second extracellular loop across many receptors as a direct binding site, a regulator for ligand entry in to the receptor transmembrane core and its impact on receptor function. Diversity in GPCR signaling can be achieved via a number of mechanisms and in this special issue 3 distinct articles highlight primary mechanisms employed by GPCR interacting partners to achieve this. Routledge et al., 2017 discuss novel functions of the receptor activity modifying proteins (RAMPs), classically known for their role in regulating trafficking and activity of the Class B calcitonin and calcitonin-like receptors, they discuss their broader function in modulating the activity of other endocrine-relevant GPCRs across subfamilies, including the calcium-sensing receptor and the estrogen responsive GPCR GPR30/GPER. GPCRs can also associate with themselves and completely distinct GPCRs to form heteromers, which can form distinct functional units with unique properties from the GPCR homomer. The existence of such complexes has historically beenmet withmuch controversy in the field,