The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT signal-transduction pathway inhibiting stress-mediated cytochrome release and caspase activation. These findings coupled with our observation that mitochondrial MT overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, "automitocrine," analogous to "autocrine" when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.

Generation of cAMP by G protein-coupled receptors (GPCRs) and its termination is currently thought to occur exclusively at the plasma membrane of cells. Under existing models of receptor regulation, this signal is primarily restricted by desensitizationof the receptors through their binding to β-arrestins. However, this paradigm is not consistent with recent observations that the parathyroid hormone receptor type 1 (PTHR) continues to stimulate cAMP production even after receptor internalization, as β-arrestins are known to rapidly bind and internalize activated PTHR. Here we show that β-arrestin1 binding prolongs rather than terminates cAMP generation by PTHR, and that cAMP generation correlates with the persistence of arrestin-receptor complexes on endosomes. We found that PTHR signaling is instead turned-off by the retromer complex, which regulates traffic of internalized receptor from endosomes to the Golgi apparatus. Thus, binding by the retromer complex regulates sustained cAMP generation triggered by an internalized GPCR.The production of cAMP by activated GPCRs is traditionally thought to originate exclusively at the plasma membrane. In most receptors studied to date elevated cAMP is rapidly extinguished by mechanisms that desensitized activated receptors through phosphorylation by G protein receptor kinases, arrestin binding that prevents further G protein coupling and can recruit cAMP specific phosphodiesterases (PDE4D) to the plasma membrane 1 , and receptor endocytosis 2 , after which desensitized receptors are recycled to the Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms ¶ Corresponding author: Jean-Pierre Vilardaga, Ph. D., Department of Pharmacology and Chemical Biology, E1357 Thomas E. Starzl Biochemical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, Tel: (412) 648 2055, Fax: (412) 648 1945, jpv@pitt.edu. Note: Supplementary information is available on the Nature Chemical Biology website. Competing interests statementThe authors have no competing financial interests to disclose. Author contributionsT.N.F performed most of the experiments with the support of V.L.W., J.A., D.S.W., S.F., and T.J.G.; J.-P.V. designed and supervised the experiments; J.-P.V. and T.N.F. analyzed the data and wrote the manuscript; all authors discussed the results and commented on the manuscript. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author Manuscript plasma membrane or trafficked to lysosomes for degradation 3 . In either case, production of cAMP is not thought to continue after GPCR internalization. However, recent studies have shown that cAMP production mediated by the PTHR in response to PTH or PTH analogs continues even after internalization of the activated receptor 4 , 5 . Together with recent work on the thyroid-stimulating hormone receptor 6 , 7 , these observati...

Physiological responses to parathyroid hormone depend on the subcellular location of receptor activity.

The paradigm that GPCRs are able to prolong or initiate cellular signalling through intracellular receptors recently emerged. Melatonin binds to G protein-coupled MT 1 and MT 2 receptors. In contrast to most other hormones targeting GPCRs, melatonin and its synthetic analogues are amphiphilic molecules easily penetrating into cells, but the existence of intracellular receptors is still unclear mainly due to a lack of appropriate tools. EXPERIMENTAL APPROACHWe therefore designed and synthesized a series of hydrophilic melatonin receptor ligands coupled to the Cy3 cyanin fluorophore to reliably monitor its inability to penetrate cells. Two compounds, one lipophilic and one hydrophilic, were then functionally characterized in terms of their affinity for human and murine melatonin receptors expressed in HEK293 cells and their signalling efficacy. KEY RESULTSAmong the different ligands, ICOA-13 showed the desired properties as it was cell-impermeant and bound to human and mouse MT 1 and MT 2 receptors. ICOA-13 showed differential activities on melatonin receptors ranging from partial to full agonistic properties for the G i /cAMP and ERK pathway and β-arrestin 2 recruitment. Notably, ICOA-13 enabled us to discriminate between G i /cAMP signalling of the MT 1 receptor initiated at the cell surface and neuronal mitochondria. CONCLUSIONS AND IMPLICATIONSWe report here the first cell-impermeant melatonin receptor agonist, ICOA-13, which allows us to discriminate between signalling events initiated at the cell surface and intracellular compartments. Detection of mitochondrial MT 1 receptors may have an important impact on the development of novel melatonin receptor ligands relevant for neurodegenerative diseases, such as Huntington disease.