Emerging paradigms in activation, signaling, and regulation of G protein-coupled receptors

Abstract

This Special Issue of The FEBS Journal brings together a set of review articles focused on recent developments in the field of GPCR biology, with particular emphasis on novel paradigms of their activation, signaling, and regulation. These articles cover a broad repertoire of cellular, physiological, and structural aspects ranging from the interaction of GPCRs with their signal transducers, allosteric modulation of these receptors with therapeutic implications, and emerging technologies aimed to probe critical aspects of receptor signaling and regulation.

The human genome encodes more than 800 different G protein-coupled receptors (GPCRs). They recognize a diverse spectrum of ligands and mediate a broad array of cellular signaling cascades resulting into a myriad of physiological responses. Understanding the ligand recognition, activation, signaling, and regulation of these receptors is of prime importance not only to decipher aspects of human physiology but also for developing novel therapeutics. There have been remarkable developments in the broad area of GPCR biology in the past several years that have uncovered the structural mechanism of their activation, resulted in new regulatory and signaling paradigms, and allowed the use of novel methodologies to explore the functional outcomes. In this backdrop, we have put together this thematic issue of The FEBS Journal focused on recent advances in the field of GPCR research. This thematic issue consists of sixteen review articles covering a broad range of topics related to GPCR signaling and regulation.

The first four review articles are focused on structural dynamics and allosteric mechanisms involved in GPCR activation. Daniel Hilger discusses the insights obtained by dynamic methods such as electron paramagnetic resonance spectroscopy into the conformational landscape of receptor activation and signaling [1]. Yin Kwan Chung and Yung Hou Wong review recent advances related to the structural activation of heterotrimeric G proteins with a particular emphasis on Gβγ signaling [2]. Nagarajan Vaidehi and coauthors present a coherent summary of recent insights gained through molecular dynamics simulation approaches to better understand the ligand−receptor interaction and ligand-specific receptor activation mechanisms [3]. Andreas Bock and Marcel Bermudez focus on the concept of biased agonism and discuss it from an allosteric point of view in the context of receptor-transducer interaction and functional outcomes [4].

The next three reviews are thematically connected, with a shared focus on regulation and signaling of GPCRs by β-arrestins (βarrs). Irene Coin and Yasmin Aydin highlight the recent advances in our understanding of how βarrs interact with activated GPCRs and regulate multiple aspects of their trafficking and signaling [5]. Jeffrey Smith and Thomas Pack discuss an exciting new paradigm of noncanonical cross-talk of G proteins and βarrs, and how the two transducers that were originally thought to be mutually exclusive coordinate with each other to fine-tune GPCR signaling [6]. Robert Lefkowitz and Anthony Nguyen discuss the structural basis of endosomal signaling from GPCRs, having recently solved the structure of a GPCR−G protein−βarr megacomplex by cryo-EM: a discovery that has changed the classical view of G protein and βarrs being mutually exclusive with respect to their interaction with GPCRs [7].

Development of novel methods, sensors and tools to probe the signaling and regulatory aspects of these versatile receptors has always been a frontier area in GPCR biology, and the next two reviews are focused on this theme. Josef Lazar and Alexey Bondar discuss the emerging approaches based on optical imaging for GPCRs and their signaling complexes at high resolution in a cellular context [8]. Mark Soave and coauthors review the recently developed clustered regularly interspaced short palindromic repeats-based platform to edit and detect endogenously expressed GPCRs, an approach that has tremendous potential to investigate GPCR signaling under native-like expression conditions [9].

The next three reviews share the common theme of physiological roles of GPCR signaling in three different contexts: neurological, metabolic, and cardiovascular regulation. Vidita Vaidya and coauthors highlight the recent discoveries that elucidate the role of distinct GPCR signaling pathways in different psychiatric disorders, and how they open up novel therapeutic opportunities [10]. Sai Prasad Pydi and coauthors focus on two major metabolic disorders, namely obesity and diabetes, and underscore the possible therapeutic avenues provided by GPCR signaling [11]. Anastasios Lymperopoulos and coauthors review the recent findings related to involvement of GPCRs, βarrs, and biased signaling in cardiovascular regulation [12].

The last four review articles discuss the emerging concepts of signaling and regulation relevant to specific receptor systems. Angela Finch and coauthors talk about the emerging pharmacology and signaling patterns of sweet taste receptors, an area that has long been in the shadows due to lack of appropriate probes [13]. Antara Banerjee and coauthors summarize the trafficking and regulation of the FSH (follicle-stimulating hormone) receptor, and how different steps in this process regulate downstream signaling responses [14]. Rithwik Ramachandran and Arundhasa Chandrabalan bring together the current conceptual framework of mechanisms that regulate the activation and signaling of proteinase activated receptors [15]. Finally, Necla Birgül and coauthors discuss the possibility of targeting insect GPCRs for the development of novel pesticides and discuss the challenges associated with such approaches [16].

On behalf of the journal, I sincerely thank all the authors for contributing such thought-provoking and cutting-edge articles for this Special Issue, the reviewers for providing important feedback to improve the articles, and our editorial and production teams for working behind the scenes to coordinate compilation of this issue in a timely and efficient manner. I do hope that the GPCR research community enjoys this Special Issue and finds the collection of articles to be timely and comprehensive in their coverage of major aspects of GPCR biology.

Abbreviation

GPCRs

G protein-coupled receptors