Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering (S.S., Ma.H., Y.T., H.H., Mi.H., R.R., S.K., M.X.M., Y.M.), and Department of Technology and Ecology, Hall of Global Environmental Studies (S.K., Y.M.), Kyoto University, Kyoto, Japan; Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan (Y.T., K.H., T.K., J.T., H.N., R.N.); Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan (A.N.); Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan (M.N.); and Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (Y.H., R.I.)
Published: March 2016
AI Article Synopsis
Article Abstract
Transient receptor potential canonical (TRPC) proteins form Ca(2+)-permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca(2+) influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca(2+) signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca(2+)-dependent transcription factor, cAMP response element-binding protein. These findings suggest that Ca(2+) signaling mediated by activation of DAG-activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a new class of synthetic neurotrophic drugs.
Co-use of xylazine with opioids is a major health threat in the United States. However, a critical knowledge gap exists in the understanding of xylazine-induced pharmacological and pathological impact. Xylazine is mostly known as an agonist of α2-adrenergic receptors (α2-ARs), but its deleterious effects on humans cannot be fully reversed by the α2-AR antagonists, suggesting the possibility that xylazine targets receptors other than α2-ARs.
The aim of the present study was to explore the role of ovarian cancer G protein-coupled receptor 1 (OGR1) in osteoclast differentiation and activity induced by extracellular acid. The impact of extracellular acidification on osteoclasts was investigated. Briefly, osteoclasts were generated from RAW 264.
Purpose: Intermittent hypoxia (IH), a defining feature of obstructive sleep apnea (OSA), is associated with heart damage and linked to transient receptor potential canonical channel 5 (TRPC5). Nonetheless, the function of TRPC5 in OSA-induced cardiac injury remains uncertain. For this research, we aimed to explore the role and potential mechanism of TRPC5 in cardiomyocyte injury induced by intermittent hypoxia.
Background: Aortic valve stenosis (AVS) is a progressive disease characterized by fibrosis, inflammation, calcification, and stiffening of the aortic valve leaflets, leading to disrupted blood flow. If untreated, AVS can progress to heart failure and death within 2 to 5 years. Uncovering the molecular mechanisms behind AVS is key for developing effective noninvasive therapies.
Two or more protein ligands may compete against each other to interact transiently with a protein receptor. While this is a ubiquitous phenomenon in cell signaling, existing technologies cannot identify its kinetic complexity because specific subpopulations of binding events of different ligands are hidden in the averaging process in an ensemble. In addition, the limited time resolution of prevailing methods makes detecting and discriminating binding events among diverse interacting partners challenging.
