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TRPM7 (ChaK1, TRP-PLIK, LTRPC7) is a ubiquitous, calcium-permeant ion channel that is unique in being both an ion channel and a serine/threonine kinase. The kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC). Here, we show that in native cardiac cells and heterologous expression systems, G alpha q-linked receptors or tyrosine kinase receptors that activate PLC potently inhibit channel activity. Numerous experimental approaches demonstrated that phosphatidylinositol 4,5-bisphosphate (PIP(2)), the substrate of PLC, is a key regulator of TRPM7. We conclude that receptor-mediated activation of PLC results in the hydrolysis of localized PIP(2), leading to inactivation of the TRPM7 channel.

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.15539. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, 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.

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 (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.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, 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.

Ischemic stroke causes a heavy health burden worldwide, with over 10 million new cases every year. Despite the high prevalence and mortality rate of ischemic stroke, the underlying molecular mechanisms for the common etiological factors of ischemic stroke and ischemic stroke itself remain unclear, which results in insufficient preventive strategies and ineffective treatments for this devastating disease. In this review, we demonstrate that transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a non-selective ion channel activated by oxidative stress, is actively involved in all the important steps in the etiology and pathology of ischemic stroke. TRPM2 could be a promising target in screening more effective prophylactic strategies and therapeutic medications for ischemic stroke. [ABSTRACT FROM AUTHOR]

TRPM7 (ChaK1, TRP-PLIK, LTRPC7) is a ubiquitous, calcium-permeant ion channel that is unique in being both an ion channel and a serine/threonine kinase. The kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC). Here, we show that in native cardiac cells and heterologous expression systems, Gαq-linked receptors or tyrosine kinase receptors that activate PLC potently inhibit channel activity. Numerous experimental approaches demonstrated that phosphatidylinositol 4,5-bisphosphate (PIP2), the substrate of PLC, is a key regulator of TRPM7. We conclude that receptor-mediated activation of PLC results in the hydrolysis of localized PIP2, leading to inactivation of the TRPM7 channel. [ABSTRACT FROM AUTHOR]

Objective: A dog atrial ultra-rapid delayed rectifier current (IKur.d) is involved in canine atrial repolarization and shares similarities with the human atrial ultra-rapid delayed rectifier (IKur). Almost no information is available about the actions of antiarrhythmic drugs on IKur.d. This study evaluated effects of ambasilide, quinidine, flecainide and verapamil on IKur.d in isolated canine atrial myocytes. Methods: Standard whole-cell patch clamp techniques were used to study the effects of multiple concentrations of each drug. Results: All drugs produced reversible concentration-, voltage- and time-dependent IKur.d inhibition. Significant effects of quinidine, flecainide and ambasilide were noted at atrial-effective antiarrhythmic concentrations in the dog. Upon the onset of a depolarizing pulse, block developed exponentially in relation to time, with the blocking rate-constant increasing with drug concentration, consistent with open-channel blockade and permitting the calculation of forward and reverse rate-constants. For all drugs, the 50% blocking concentration (EC50) showed significant voltage-dependence, decreasing at more positive potentials. The magnitude of voltage-dependent block was directly related to the degree of drug-induced shift in the voltage dependence of activation (r=0.97), pointing to open-channel block as a mechanism for voltage-dependent action. An additional component of voltage-dependence suggested that blocking sites were subjected to 17–21% of the transmembrane voltage field. Conclusions: Ambasilide, quinidine, flecainide and verapamil inhibit IKur.d, with preferential action on the open state. IKur.d inhibition may play a role in antiarrhythmic effects in canine atrial arrhythmia models. Comparisons between the effects of these drugs on IKur.d and previously studied effects on IKur suggest potential opportunities for investigating the molecular structural determinants of drug-blocking action on atrial-specific ultrarapid delayed rectifiers. [ABSTRACT FROM PUBLISHER]

Excitotoxicity induced by NMDA receptor (NMDAR) activation is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical trials. Here, we reveal an unexpected mechanism underlying NMDAR-mediated neurotoxicity, which leads to the identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDAR-induced excitotoxicity is enhanced by physical and functional coupling of NMDAR to an ion channel TRPM2 upon ischemic insults. TRPM2-NMDAR association promotes the surface expression of extrasynaptic NMDARs, leading to enhanced NMDAR activity and increased neuronal death. We identified a specific NMDAR-interacting motif on TRPM2 and designed a membrane-permeable peptide to uncouple the TRPM2-NMDAR interaction. This disrupting peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to mitigate excitotoxic neuronal death without directly targeting NMDARs. [Display omitted] • TRPM2 physically and functionally interacts with extrasynaptic NMDAR • TRPM2-NMDAR interaction exacerbates excitotoxicity during ischemic stroke • TRPM2 recruits PKCγ, thereby increasing NMDAR's surface expression • Uncoupling TRPM2-NMDAR interaction attenuates ischemic brain injury Zong et al. discover an unexpected association between the oxidative stress-sensitive ion channel TRPM2 and the extrasynaptic NMDA receptor (NMDAR) in the neurons, which enhances excitotoxicity during ischemic brain injury. Neuron-specific knockout of TRPM2 or uncoupling of the TRPM2-NMDAR association using an interfering peptide protects mice against ischemic stroke. [ABSTRACT FROM AUTHOR]

Introduction: A variety of cardiovascular diseases stem from the manifestations of subclinical atherosclerosis, whose growth is fueled by inflammatory cytokines produced by macrophage-derived foam cells. A better understanding of the mechanisms underlying atherosclerosis will provide novel insights on potential therapeutic approaches for atherosclerosis associated cardiovascular diseases. The Ca2+-permeable TRPM2 which is activated by various reactive oxygen species (ROS) under stress conditions, is highly expressed in monocytes and macrophages. Our objective is to understand how TRPM2 in monocytes/macrophages mediates inflammation in atherosclerosis. Our hypothesis is that monocyte/macrophage TRPM2 is activated in the oxidative environment of atherosclerosis, and blocking TRPM2 will attenuates initiation and progression of atherosclerosis, thereby mitigating atherosclerotic cardiovascular disease. Methods: ApoE-deficient mice with Trpm2 deletion (APOE-TRPM2 double knockout: DKO) mice were fed with a high fat diet (HFD) to generate atherosclerosis. TRPM2 activity was measured by patch-clamp electrophysiology using peritoneal macrophages (PMs) obtained from DKO mice fed with HFD. Peripheral blood cells were collected from the tail vein and analyzed by flow cytometry. Results: We found that atherosclerosis plaque area was significantly reduced in HFD-fed DKO mice in comparison with the HFD-fed ApoE-KO mice (p<0.001). The TRPM2 channel activity and TRPM2 mediated Ca2+ entry in macrophages were markedly higher in ApoE-KO mice fed with HFD than the ApoE-KO mice fed with normal chow, suggesting that TRPM2 may play a role in the atherosclerosis (p<0.05). Moreover, TRPM2 deletion drastically reduced IL-β production in PMs induced by LPS. Furthermore, we found that Trpm2-KO led to a 17% reduction of the inflammatory circulating myeloid cells in the ApoE-TRPM2 DKO mice compared to ApoE-KO mice fed with HFD (p<0.005). Conclusions: Our results indicate that deletion of TRPM2 reduces atherosclerotic plaques. Both inflammatory cytokine IL-1β production and inflammatory macrophages are reduced by TRPM2 deletion, indicating that the mechanisms by which TRPM2 inhibition deletion reduces atherosclerosis is through inhibiting inflammation during the atherosclerosis. As oxidative stress is a hallmark of atherosclerotic plaques, targeting monocyte/macrophage TRPM2 may serve as a novel approach to halt initiation and progression of atherosclerosis, as well as atherosclerotic cardiovascular diseases. [ABSTRACT FROM AUTHOR]