Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
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PMID:Vascular biology of endothelin. 988 41

The Ca(2+)-permeable, nonselective cation channel TRPC6 is gated via phospholipase C-activating receptors and has recently been implicated in hypoxia-induced pulmonary vasoconstriction (HPV), idiopathic pulmonary hypertension and focal segmental glomerulosclerosis (FSGS). Therefore, TRPC6 is a promising target for pharmacological interference. To identify and develop TRPC6-blocking compounds, we screened the Chembionet library, a collection of 16,671 chemically diverse drug-like compounds, for biological activity to prevent the 1-oleoyl-2-acetyl-sn-glycerol-triggered Ca(2+) influx in a stably transfected HEK(TRPC6-YFP) cell line. Hits were validated and characterised by fluorometric and electrophysiological methods. Six compounds displayed inhibitory potency at low micromolar concentrations, lack of cytotoxicity and blocked the receptor-dependent mode of TRPC6 activation. The specificity was tested towards closely (TRPC3 and TRPC7) and more distantly related TRP channels. One of the compounds, 8009-5364, displayed a 2.5-fold TRPC6-selectivity compared to TRPC3, and almost no inhibition of TRPC7 or the other TRP channels tested. Block of native TRPC3/6-like responses was confirmed in dissociated pulmonary artery smooth muscle cells. Two non-polar blockers effectively suppressed the HPV responses in the perfused mouse lung model. We conclude that pharmacological targeting of TRPC6 is feasible and provide a promising concept to treat pulmonary diseases that are characterised by excessive hypoxic vasoconstriction.
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PMID:Novel pharmacological TRPC inhibitors block hypoxia-induced vasoconstriction. 2228 Aug 12