oa Editorial [Hot topic: New Frontiers in G Protein-Coupled Receptor Regulation of Neurological Disorders (Guest Editor: Stuart Maudsley)]

Heptahelical G protein-coupled receptors (GPCR) constitute one of the most studied groups of proteins in the genome. Intense investigation of this protein superfamily is more than justified as therapeutics targeting the GPCR superfamily account for nearly half of the current pharmacopeia. Along with many years of exemplary scientific research into the activity of GPCRs has come the creeping concept of diminishing novel scientific returns based on this research, an oft-quoted phrase among GPCR molecular biologists represents this, i.e., ‘is there anything else we can learn?’ As with all such dogmatic and pessimistic statements the answer is a resounding no. It seems that the more we understand and appreciate the importance of GPCRs in both physiology and pharmacology, the more we realize in essence how little we know of their true, in vivo, nature. Our current generation of GPCR biologists are now tackling this important issue, as they start to step away from more artificial recombinant systems in attempting to understand and investigate GPCR biology in true physiological settings. One of the most important aspects of extending our appreciation of physiological GPCR activity is the cellular or tissue context that the receptor is expressed in. This is nowhere more important than in the central nervous system (CNS) as multiple, highly polarized, cell types and tissues are in a much smaller area than most peripheral tissues. In this special issue we have attempted to look to the future of GPCR research and investigation in this important growth area. We shall explore the huge potential of targeting multiple diverse CNS GPCR systems as well as how our understanding of the true in situ nature of GPCRs in the CNS, at the modulatory and protein-protein interaction level, will greatly assist our development of future neurotherapeutics. Exploring the possibilities of the complex CNS GPCR environment has allowed us to appreciate the presence of novel receptor system therapeutic targets such as those for: vasoactive intestinal peptide (White et al.), metabotropic glutamatergics (Ribeiro et al.), gonadotropin-releasing hormone (Wang et al.), cannabinoids (Bisogno & Di Marzo), tachykinins (Pantaleo et al.), dopamine (Cadet et al.), and Ghrelin (Cong et al.). The rational targeting of these important CNS systems has the potential to treat conditions as varied as neurodegeneration, aging, stress resistance, and the neurological impacts of metabolic syndromes. In addition to appreciating how we can therapeutically target important diverse GPCR systems in the CNS, in this special issue we have also addressed important issues related to connecting our molecular understanding of how GPCRs truly function in complex and diverse cellular environments. To this end we present in-depth studies into the physiological and pharmacological importance of receptor hetereomerization of GPCRs in the CNS (Albizu et al.; Ferre et al.) as well as the importance of how multiple neuronal receptor modulatory and trafficking processes can affect GPCR-based neurophysiological activities (Lopez-Gimenez & Milligan; Lopez de Maturana & Sanchez-Pernaute, Bunnett & Cottrell). With respect to this most important of therapeutic targets in the CNS it seems that with further research we may exponentially uncover yet more and more detail of the workings of this protein superfamily.