The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 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 (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 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/bph.15538. 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‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mouse 3T3-L1 and in human subcutaneous (hSC) and omental (hOM) adipocytes. In vivo, the influence of obestatin on glucose metabolism was assessed in mice fed an HFD for 8 wk. 3T3-L1, hSC, and hOM preadipocytes and adipocytes secreted obestatin and showed specific binding for the hormone. Obestatin prevented apoptosis in 3T3-L1 preadipocytes by increasing phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. In both mice and human adipocytes, obestatin inhibited isoproterenol-induced lipolysis, promoted AMP-activated protein kinase phosphorylation, induced adiponectin, and reduced leptin secretion. Obestatin also enhanced glucose uptake in either the absence or presence of insulin, promoted GLUT4 translocation, and increased Akt phosphorylation and sirtuin 1 (SIRT1) protein expression. Inhibition of SIRT1 by small interfering RNA reduced obestatin-induced glucose uptake. In HFD-fed mice, obestatin reduced insulin resistance, increased insulin secretion from pancreatic islets, and reduced adipocyte apoptosis and inflammation in metabolic tissues. These results provide evidence of a novel role for obestatin in adipocyte function and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions.

Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs.

Recent, compelling evidence indicates that kisspeptins, the products of KiSS-1 gene, and their receptor GPR54, represent key elements in the neuroendocrine control of reproduction, and that they act primarily by regulating gonadotrophin-releasing hormone (GnRH) secretion at the hypothalamus. Conversely, and despite earlier reports showing GPR54 expression in the pituitary, the potential physiological roles of kisspeptins at this gland have remained elusive. To clarify this issue, cultures of rat pituitary cells were used to evaluate expression of KiSS-1 and GPR54, and to monitor the ability of kisspeptin-10 to stimulate Ca(2+) responses in gonadotrophs and to elicit luteinising hormone (LH) secretion in vitro. The results obtained show that both GPR54 and KiSS-1 are expressed in the pituitary of peripubertal male and female rats. Moreover, kisspeptin-10 induced a rise in free cytosolic Ca(2+) concentration ([Ca(2+)](i)) in approximately 10% of male rat pituitary cells. Intriguingly, kisspeptin-responsive cells included not only gonadotrophs, in which a 62.8 +/- 16.0%[Ca(2+)](i) rise was observed, but also somatotrophs, wherein kisspeptin induced a 60.3 +/- 5.5%[Ca(2+)](i) increase. Accordingly, challenge of dispersed pituitary cells with increasing kisspeptin-10 concentrations induced dose-related LH and growth hormone (GH) secretory responses, which were nevertheless of lower magnitude than those evoked by the primary regulators GnRH and GH-releasing hormone, respectively. In particular, 10(-8) M kisspeptin caused maximal increases in LH release (218.7 +/- 23.6% and 180.4 +/- 7.2% in male and female rat pituitary cells, respectively), and also stimulated maximally GH secretion (181.9 +/- 14.9% and 260.2 +/- 15.9% in male and female rat pituitary cells, respectively). Additionally, moderate summation of kisspeptin- and GnRH-induced LH responses was observed after short-term incubation of male rat pituitary cells. In conclusion, our results provide unequivocal evidence that kisspeptins exert direct pituitary effects in peripubertal male and female rats and suggest a possible autocrine/paracrine mode of action. The precise relevance and underlying mechanisms of this potential new actions of kisspeptins (i.e. the direct modulation of gonadotrophic and somatotrophic axis at the pituitary) deserve further analysis.

The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with native-ghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cancer.

Our results demonstrate the existence of two previously unidentified sst5 spliced variants with distinct distribution in normal tissues and pituitary tumors, unique ligand-selective signaling properties, and subcellular distribution, which could contribute to somatostatin and cortistatin signaling in normal and tumoral cells.

Ghrelin acts as an endocrine link connecting physiological processes regulating food intake, body composition, growth, and energy balance. Ghrelin is the only peptide known to undergo octanoylation. The enzyme mediating this process, ghrelin O-acyltransferase (GOAT), is expressed in the gastrointestinal tract (GI; primary source of circulating ghrelin) as well as other tissues. The present study demonstrates that stomach GOAT mRNA levels correlate with circulating acylatedghrelin levels in fasted and diet-induced obese mice. In addition, GOAT was found to be expressed in both the pituitary and hypothalamus (two target tissues of ghrelin's actions), and regulated in response to metabolic status. Using primary pituitary cell cultures as a model system to study the regulation of GOAT expression, we found that acylated-ghrelin, but not desacyl-ghrelin, increased GOAT expression. In addition, growth-hormone-releasing hormone (GHRH) and leptin increased, while somatostatin (SST) decreased GOAT expression. The physiologic relevance of these later results is supported by the observation that pituitary GOAT expression in mice lacking GHRH, SST and leptin showed opposite changes to those observed after in vitro treatment with the corresponding peptides. Therefore, it seems plausible that these hormones directly contribute to the regulation of pituitary GOAT. Interestingly, in all the models studied, pituitary GOAT expression paralleled changes in the expression of a dominant spliced-variant of ghrelin (In2-ghrelin) and therefore this transcript may be a primary substrate for pituitary GOAT. Collectively, these observations support the notion that the GI tract is not the only source of acylated-ghrelin, but in fact locally-produced des-acylated-ghrelin could be converted to acylated-ghrelin within target tissues by locally active GOAT, to mediate its tissue-specific effects.