The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 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/10.1111/bph.16176. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, 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-2023, and supersedes data presented in the 2021/22, 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.

Microglia Phenotypes in Aging and Neurodegenerative Diseases.

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and Other Protein Targets.

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 (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.15537. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are six areas of focus: G protein-coupled receptors, 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.

RGS10 physically and functionally interacts with STIM2 and requires store-operated calcium entry to regulate pro-inflammatory gene expression in microglia.

Chronic activation of microglia is a driving factor in the progression of neuroinflammatory diseases, and mechanisms that regulate microglial inflammatory signaling are potential targets for novel therapeutics. Regulator of G protein Signaling 10 is the most abundant RGS protein in microglia, where it suppresses inflammatory gene expression and reduces microglia-mediated neurotoxicity. In particular, microglial RGS10 downregulates the expression of pro-inflammatory mediators including cyclooxygenase 2 (COX-2) following stimulation with lipopolysaccharide (LPS). However, the mechanism by which RGS10 affects inflammatory signaling is unknown and is independent of its canonical G protein targeted mechanism. Here, we sought to identify non-canonical RGS10 interacting partners that mediate its anti-inflammatory mechanism. Through RGS10 co-immunoprecipitation coupled with mass spectrometry, we identified STIM2, an endoplasmic reticulum (ER) localized calcium sensor and a component of the store-operated calcium entry (SOCE) machinery, as a novel RGS10 interacting protein in microglia. Direct immunoprecipitation experiments confirmed RGS10-STIM2 interaction in multiple microglia and macrophage cell lines, as well as in primary cells, with no interaction observed with the homologue STIM1. We further determined that STIM2, Orai channels, and the calcium-dependent phosphatase calcineurin are essential for LPS-induced COX-2 production in microglia, and this pathway is required for the inhibitory effect of RGS10 on COX-2. Additionally, our data demonstrated that RGS10 suppresses SOCE triggered by ER calcium depletion and that ER calcium depletion, which induces SOCE, amplifies pro-inflammatory genes. In addition to COX-2, we also show that RGS10 suppresses the expression of pro-inflammatory cytokines in microglia in response to thrombin and LPS stimulation, and all of these effects require SOCE. Collectively, the physical and functional links between RGS10 and STIM2 suggest a complex regulatory network connecting RGS10, SOCE, and pro-inflammatory gene expression in microglia, with broad implications in the pathogenesis and treatment of chronic neuroinflammation.

RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein-Independent Mechanism.

The small regulator of G protein signaling protein RGS10 is a key regulator of neuroinflammation and ovarian cancer cell survival; however, the mechanism for RGS10 function in these cells is unknown and has not been linked to specific G protein pathways. RGS10 is highly enriched in microglia, and loss of RGS10 expression in microglia amplifies production of the inflammatory cytokine tumor necrosis factor α (TNFα) and enhances microglia-induced neurotoxicity. RGS10 also regulates cell survival and chemoresistance of ovarian cancer cells. Cyclooxygenase-2 (COX-2)-mediated production of prostaglandins such as prostaglandin E2 (PGE2) is a key factor in both neuroinflammation and cancer chemoresistance, suggesting it may be involved in RGS10 function in both cell types, but a connection between RGS10 and COX-2 has not been reported. To address these questions, we completed a mechanistic study to characterize RGS10 regulation of TNFα and COX-2 and to determine if these effects are mediated through a G protein-dependent mechanism. Our data show for the first time that loss of RGS10 expression significantly elevates stimulated COX-2 expression and PGE2 production in microglia. Furthermore, the elevated inflammatory signaling resulting from RGS10 loss was not affected by Gαi inhibition, and a RGS10 mutant that is unable to bind activated G proteins was as effective as wild type in inhibiting TNFα expression. Similarly, suppression of RGS10 in ovarian cancer cells enhanced TNFα and COX-2 expression, and this effect did not require Gi activity. Together, our data strongly indicate that RGS10 inhibits COX-2 expression by a G protein-independent mechanism to regulate inflammatory signaling in microglia and ovarian cancer cells.