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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL096411-05
Application #
8448105
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F2))
Program Officer
Meadows, Tawanna
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$116,712
Indirect Cost
$8,645
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Adebiyi, Adebowale (2014) RGS2 regulates urotensin II-induced intracellular Ca2+ elevation and contraction in glomerular mesangial cells. J Cell Physiol 229:502-11
Narayanan, Damodaran; Adebiyi, Adebowale; Jaggar, Jonathan H (2012) Inositol trisphosphate receptors in smooth muscle cells. Am J Physiol Heart Circ Physiol 302:H2190-210
Adebiyi, Adebowale; Narayanan, Damodaran; Jaggar, Jonathan H (2011) Caveolin-1 assembles type 1 inositol 1,4,5-trisphosphate receptors and canonical transient receptor potential 3 channels into a functional signaling complex in arterial smooth muscle cells. J Biol Chem 286:4341-8
Bannister, John P; Thomas-Gatewood, Candice M; Neeb, Zachary P et al. (2011) Ca(V)1.2 channel N-terminal splice variants modulate functional surface expression in resistance size artery smooth muscle cells. J Biol Chem 286:15058-66
Thomas-Gatewood, Candice; Neeb, Zachary P; Bulley, Simon et al. (2011) TMEM16A channels generate Caýýýýý-activated Clýýý currents in cerebral artery smooth muscle cells. Am J Physiol Heart Circ Physiol 301:H1819-27
Adebiyi, Adebowale; McNally, Elizabeth M; Jaggar, Jonathan H (2011) Vasodilation induced by oxygen/glucose deprivation is attenuated in cerebral arteries of SUR2 null mice. Am J Physiol Heart Circ Physiol 301:H1360-8
Zhao, Guiling; Neeb, Zachary P; Leo, M Dennis et al. (2010) Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells. J Gen Physiol 136:283-91
Adebiyi, Adebowale; Zhao, Guiling; Narayanan, Damodaran et al. (2010) Isoform-selective physical coupling of TRPC3 channels to IP3 receptors in smooth muscle cells regulates arterial contractility. Circ Res 106:1603-12
Bannister, John P; Adebiyi, Adebowale; Zhao, Guiling et al. (2009) Smooth muscle cell alpha2delta-1 subunits are essential for vasoregulation by CaV1.2 channels. Circ Res 105:948-55