1521-0111/90/5/570–572$25.00 http://dx.doi.org/10.1124/mol.116.106062 MOLECULAR PHARMACOLOGY Mol Pharmacol 90:570–572, November 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics COMMENTARY—A LATIN AMERICAN PERSPECTIVE ON G PROTEIN-COUPLED RECEPTORS A Latin American Perspective on G Protein–Coupled Receptors André S. Pupo and J. Adolfo García-Sáinz Department of Pharmacology, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, São Paulo, Brazil (A.S.P.); and Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico (J.A.G.-S.) Received July 8, 2016; accepted August 25, 2016 ABSTRACT G protein–coupled receptors are sensors that interact with a large variety of elements, including photons, ions, and large proteins. Not surprisingly, these receptors participate in the numerous normal physiologic processes that we refer to as health and in its perturbations that constitute disease. It has been estimated that a large percentage of drugs currently used in therapeutics target these proteins, and this percentage is larger when illegal drugs are included. The state of the art in this field can be defined with the oxymoron “constant change,” and enormous progress has been made in recent years. A group of scientists working in Latin America were invited to contribute minireviews for this special section to present some of the work performed in this geographical region and foster further international collaboration. Perspective G protein–coupled receptors (GPCRs) constitute one of the main protein families through which cells sense the external environment (e.g., light, odors, tastants, or mating factors [yeast]) and the milieu intérieur of multicellular organisms (e.g., hormones, neurotransmitters, autacoids, and other mediators). These receptors made their appearance approxi- mately 1.2 billion years ago after the separation of alveolates, whose genomes do not contain sequences directly related to GPCRs, from GPCR-expressing fungi and plants (Fredriksson and Schiöth, 2005). In known genomes, GPCR sequences are more abundant in nematodes and arthropods compared with plants or fungi, and even more so in vertebrates and mam- mals. These molecular entities are considered a tremendous success in the context of evolution; GPCRs can represent as much as 5% of the coding sequences in the genomes of some species (Fredriksson and Schiöth, 2005). In humans, the number of distinct GPCRs is estimated to be approximately 800, but many are orphan receptors since we do not yet know their natural ligands and functions (Fredriksson et al., 2003; Fredriksson and Schiöth, 2005). Great efforts are in progress to classify these receptors structurally and functionally (Fredriksson et al., 2003; Fredriksson and Schiöth, 2005; see also http://www.guidetopharmacology.org/GRAC/FamilyDis- playForward?familyId5694). A dramatic evolution of thought and discovery has taken place over the last 100 years as researchers have begun defining these proteins as molecular entities instead of mere concepts. This has changed the understanding of physiologic and pathologic processes, the perception of cellular functions, medical education, and even clinical practice. A reflection of this ongoing revolution is the fact that two researchers, Robert J. Lefkowitz and Brian Kobilka, were awarded the Nobel Prize in Chemistry in 2012 (Kobilka, 2013; Lefkowitz, 2013; see also the corresponding sections on the Nobel Prize webpage at http://www.nobelprize.org/). The number of laboratories that have contributed to this field and continue to do so is enormous and is likely to continue growing. As anticipated, GPCRs mediate a plethora of functions and are involved in the pathogenesis of many diseases. This latter aspect is frequently called the “dark side” of GPCRs but it is actually an opportunity that allows for therapeutic possibili- ties through pharmacological intervention. Advances using classic and molecular approaches are changing pharmacology. For example, the agonist (on)–antagonist (off) paradigm of how ligands modulate GPCR activity is now substituted by new ideas proposing that ligands induce a variety of active and inactive receptor conformations (see for example Audet and Bouvier, 2012; Manglik and Kobilka, 2014; Thanawala et al., 2014; Huang et al., 2015; DeVree et al., 2016). Operationally, these mechanisms might lead to different drug behaviors increasing the repertoire of pharmacodynamic possibilities, including full, partial, biased, and inverse agonism, as well as antagonism, allosteric modulation, and induction of internal- ization/degradation, among others (see for example Kenakin, 2009, 2015; Christopoulos, 2014; Roth and Bruggeman, 2014). This knowledge already has a profound effect on human dx.doi.org/10.1124/mol.116.106062. ABBREVIATIONS: GPCR, G protein–coupled receptor; TRV130, N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan- 9-yl]ethanamine. 570 at ASPET Journals on February 28, 2022 molpharm.aspetjournals.org Downloaded from