oa Editorial [Hot Topic: G protein-Coupled Receptors Interacting Proteins: Towards the Druggable Interactome (Guest Editor: Francisco Ciruela)]

G protein-coupled receptors (GPCRs) are heptaspanning membrane proteins that mediate physiological responses to a plethora of signals including hormones, neurotransmitters and exogenous sensory stimuli perceived by the senses (i.e. light, odor and taste) [1]. Classically, the mechanism by which GPCR transduce extracellular signals into cellular changes was envisaged as a plain linear model, thus the extracellular agonist ‘ligand’ binds to and switches the receptor from an inactive to an active state conformation, and the activated receptor catalyzes the activation of guanine nucleotide binding proteins (G proteins) [2]. The activation of the heterotrimeric G protein (Gαβγ) involved the exchange of a GDP for a GTP molecule on the α-subunit, thus leading to the G protein dissociation into its α and βγ subunits. Interestingly, both Gα and Gβγ subunits can activate or inhibit effector enzymes (i.e. adenylyl cyclases, phosphodiesterases, phospholipases) and ion channels which in turn trigger multiple intracellular signaling pathways that modulate cell functions in body systems as diverse as the skeletal, endocrine, cardiovascular and nervous systems, among others [3]. In cells, most of the functions are mediated by multiprotein complexes. Interestingly, apart from binding to and activating the G proteins, GPCRs associate with a large array of other GPCR-interacting proteins (GIPs). These, membrane associated or intracellular GIPs, contain structural interacting domains that allow, under certain circumstances, the formation of large functional multiprotein complexes that are essential for both G protein-dependent and -independent signalling. Eventually, these GIPs may simply act as scaffold proteins that anchor the GPCRs to specific plasma membrane domains, thus contributing to the subcellular GPCR compartmentalization, and also participating in the GPCR trafficking to and from the plasma membrane. Overall, GIPs play a key role in GPCR biology as they fine-tune the receptor's function by impinging in its trafficking, localization and/or pharmacological properties [4]. Recently, special attention has been paid to GIPs as they might potentially evolve as drug targets [4, 5]. Therefore, here we intended to focus on the emerging evidence of GPCR interactions with scaffolding, cytoskeletal and signalling proteins that will play a key role in the targeting, anchoring and functioning of these receptors in the plasma membrane, thus constituting a pharmacological target for drug intervention. Accordingly, the present issue of Current Drug Targets aims to bring together a number of leading experts in the field of GPCRs in order to summarize the main aspects of the state of the art GIPs of some representative GPCRs. Thus, ten excellent papers compose this special edition which revolves around the GIPs of the mammalian dim-light photoreceptor rhodopsin, the adrenergic receptors, the 5-hydroxytryptamine (5-HT) receptors, the muscarinic acetylcholine (mACh) receptors, the dopamine receptors, the parathyroid hormone (PTH) receptors, the opioid receptor, the γ-aminobutyric acid (GABA) type B receptor, the metabotropic glutamate (mGlu) receptors, and the small family B1 GPCR (secretin-like receptors) which includes within others the vasoactive intestinal peptide (VPAC) receptors, the secretin (SEC) receptors, and the corticotropin-releasing factor (CRF) receptors. Thus, we hope that this timely focused issue summarizing our current knowledge on GIPs will be of interest to a wide range of readers of the journal interested in the GPCR field. Finally, I would like to express my best thanks to all the contributing authors and co-authors of this issue for their commitment, time, experience and patience. Also, my special thanks to the anonymous reviewers for their excellent contributions to the peer-review process. In addition, I want to express my special gratitude to Professor Francis J. Castellino, editor-in-chief of Current Drug Targets, for giving me this opportunity, and to the staff at Bentham Science for their assistance and cooperation.