Vasoregulation by IP3 receptor coupling to TRPC channels

通过 IP3 受体与 TRPC 通道偶联进行血管调节

• 批准号: 8448105
• 负责人: Adebowale Adebiyi
• 金额: $ 11.67万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448105
• 关键词: 11p; ATP phosphohydrolase; Arteries; Attenuated; Biological Assay; Blood Pressure; Blood Vessels; Blood flow; Calcium; Caliber; Cations; Caveolae; Cell membrane; Cholesterol; Co-Immunoprecipitations; Computer software; Coupled; Coupling; Data; Detection; Electrophysiology (science); Endothelium; Energy Transfer; Event; Fluorescence Resonance Energy Transfer; Fura-2; Genes; Glass; ITPR1 gene; Image; Immunofluorescence Immunologic; Inositol; Measures; Mediating; Membrane; Membrane Potentials; Microelectrodes; Molecular; Molecular Biology; Mus; Muscle Cells; Myography; Organ; Pathway interactions; Phospholipase C; Physiology; Principal Investigator; Protein Isoforms; Proteins; Publishing; Receptor Activation; Regulation; Reporting; Role; Sarcoplasmic Reticulum; Second Messenger Systems; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Structural Protein; TRP channel; TRPC3 ion channel; Techniques; Testing; Tissues; Vasoconstrictor Agents; caveolin 1; cerebral artery; computerized data processing; constriction; methyl-beta-cyclodextrin; novel; patch clamp; ratiometric; receptor; receptor coupling; research study; second messenger; small hairpin RNA; vasoconstriction; voltage

Arterial diameter, a principal modulator of systemic blood pressure and organ blood flow is regulated by changes in the contractility of arterial myocytes. The contractile status of arterial myocytes is determined by several local and global intracellular calcium ([Ca2+]i) signals. Ca2+ signal and diameter regulation by inositol 1,4,5-trisphophate (IP3), a phospholipase C-generated second messenger is poorly understood. The conventional view has been that IP3 constricts arteries by stimulating sarcoplasmic reticulum (SR) Ca2+ release in myocytes. Our recently published data indicated a novel mechanism of IP3-induced vasoconstriction that occurred independently of SR Ca2+ release, and via IP3 receptor (IP3R)- and canonical transient receptor potential (TRPC) 3-dependent cation current (ICat) activation. However, mechanisms by which IP3R activation stimulates TRPC channels in arterial myocytes to regulate arterial diameter are unclear. Preliminary data suggest that physical coupling between myocyte IP3Rs and TRPC3 channels regulates IP3-induced vasoconstriction. Data also indicate that arterial myocyte caveolae facilitate this IP3R-TRPC channel vasoregulatory mechanism. The central hypothesis of this proposal is that in cerebral artery myocytes, caveolae facilitate TRPC3 channel coupling with IP3Rs to mediate vasoconstrictor and IP3-induced membrane depolarization, voltage-dependent Ca2+ channel activation, [Ca2+]i elevation, and contraction. This proposal will investigate 3 specific aims: Aim 1 will test the hypothesis that in cerebral artery myocytes, IP3R to TRPC3 channel physical coupling is required for IP3-induced ICat activation. Aim 2 will test the hypothesis that IP3R to TRPC3 coupling mediates IP3-induced membrane depolarization, [Ca2+]i elevation, and constriction in cerebral arteries. Aim 3 will examine the hypothesis that arterial myocyte caveolae mediate physical and functional coupling of TRPC3 channels to IP3Rs. Experiments to study these aims will integrate techniques performed at molecular, cellular, and intact tissue levels, including Ca2+ imaging, FRET, electrophysiology, pressurized artery myography, and gene suppression.

动脉直径是调节全身血压和器官血流的主要调节因子