Protein kinase C regulates vascular myogenic tone through activation of TRPM4

2007 ◽  
Vol 292 (6) ◽  
pp. H2613-H2622 ◽  
Author(s):  
Scott Earley ◽  
Stephen V. Straub ◽  
Joseph E. Brayden
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Antisense Oligonucleotides ◽  
Cerebral Arteries ◽  
Myogenic Tone ◽  
Kinase C ◽  
Intracellular Ca ◽  
Cell Depolarization ◽  
Stimulation Of

Myogenic vasoconstriction results from pressure-induced vascular smooth muscle cell depolarization and Ca2+ influx via voltage-dependent Ca2+ channels, a process that is significantly attenuated by inhibition of protein kinase C (PKC). It was recently reported that the melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressure-induced smooth muscle depolarization and constriction in cerebral arteries. Interestingly, PKC activity enhances the activation of cloned TRPM4 channels expressed in cultured cells by increasing sensitivity of the channel to intracellular Ca2+. Thus we postulated that PKC-dependent activation of TRPM4 might be a critical mediator of vascular myogenic tone. We report here that PKC inhibition attenuated pressure-induced constriction of cerebral vessels and that stimulation of PKC activity with phorbol 12-myristate 13-acetate (PMA) enhanced the development of myogenic tone. In freshly isolated cerebral artery myocytes, we identified a Ca2+-dependent, rapidly inactivating, outwardly rectifying, iberiotoxin-insensitive cation current with properties similar to those of expressed TRPM4 channels. Stimulation of PKC activity with PMA increased the intracellular Ca2+ sensitivity of this current in vascular smooth muscle cells. To validate TRPM4 as a target of PKC regulation, antisense technology was used to suppress TRPM4 expression in isolated cerebral arteries. Under these conditions, the magnitude of TRPM4-like currents was diminished in cells from arteries treated with antisense oligonucleotides compared with controls, identifying TRPM4 as the molecular entity responsible for the PKC-activated current. Furthermore, the extent of PKC-induced smooth muscle cell depolarization and vasoconstriction was significantly decreased in arteries treated with TRPM4 antisense oligonucleotides compared with controls. We conclude that PKC-dependent regulation of TRPM4 activity contributes to the control of cerebral artery myogenic tone.

Increased Ca2+ sensitivity as a key mechanism of PKC-induced constriction in pressurized cerebral arteries

1999 ◽  
Vol 277 (3) ◽  
pp. H1178-H1188 ◽  
Author(s):  
Natalia I. Gokina ◽  
Harm J. Knot ◽  
Mark T. Nelson ◽  
George Osol
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Channel Blocker ◽  
Cerebral Arteries ◽  
Intraluminal Pressure ◽  
Arterial Diameter ◽  
Kinase C ◽  
Voltage Dependent ◽  
Intracellular Ca

The effects of activating protein kinase C (PKC) with indolactam V (Indo-V) and 1,2-dioctanoyl- sn-glycerol (DOG) on smooth muscle intracellular Ca2+concentrations ([Ca2+]i) and arterial diameter were determined using ratiometric Ca2+ imaging and video edge detection of pressurized rat posterior cerebral arteries. Elevation of intraluminal pressure from 10 to 60 mmHg resulted in an increase in [Ca2+]ifrom 74 ± 5 to 219 ± 8 nM and myogenic constriction. Application of Indo-V (0.01–3 μM) or DOG (0.1–30 μM) induced constriction and decreased [Ca2+]ito 140 ± 11 and 127 ± 12 nM, respectively, at the highest concentrations used. In the presence of Indo-V, the dihydropyridine Ca2+-channel-blocker nisoldipine produced nearly maximum dilation and decreased [Ca2+]ito 97 ± 7 nM. In α-toxin-permeabilized arteries, the constrictor effects of Indo-V and DOG were not observed in the absence of Ca2+. Both PKC activators significantly increased the degree of constriction of permeabilized arteries at different [Ca2+]i. We conclude that 1) Indo-V- or DOG-induced constriction of pressurized arteries requires Ca2+ influx through voltage-dependent Ca2+ channels, and 2) PKC-induced constriction of pressurized rat cerebral arteries is associated with a decrease in [Ca2+]i, suggesting an increase in the Ca2+sensitivity of the contractile process.

Prolactin stimulation of protein kinase C activity in rat aortic smooth muscle

Life Sciences ◽  
1989 ◽  
Vol 44 (23) ◽  
pp. 1787-1792 ◽  
Author(s):  
Marie Donabella Sauro ◽  
Arthur R. Buckley ◽  
Diane Haddock Russell ◽  
David F. Fitzpatrick
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Aortic Smooth Muscle ◽  
Kinase C ◽  
Protein Kinase C Activity ◽  
Stimulation Of

scholarly journals Mechanisms regulating cAMP-mediated growth of bovine neonatal pulmonary artery smooth muscle cells

1999 ◽  
Vol 276 (6) ◽  
pp. L1010-L1017 ◽  
Author(s):  
Alexandra Guldemeester ◽  
Kurt R. Stenmark ◽  
George H. Brough ◽  
Troy Stevens
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Angiotensin Ii ◽  
Protein Kinase ◽  
Pulmonary Artery ◽  
Growth Responses ◽  
Camp Content ◽  
Kinase C ◽  
Pulmonary Artery Smooth Muscle ◽  
Stimulation Of

Neonatal pulmonary artery smooth muscle cells (PASMCs) exhibit enhanced growth capacity and increased growth responses to mitogenic stimuli compared with adult PASMCs. Because intracellular signals mediating enhanced growth responses in neonatal PASMCs are incompletely understood, we questioned whether 1) Gq agonists increase cAMP content and 2) increased cAMP is proproliferative. Endothelin-1 and angiotensin II increased both cAMP content and proliferation in neonatal but not in adult PASMCs. Inhibition of protein kinase C and protein kinase A activity nearly eliminated the endothelin-1- and angiotensin II-induced growth of neonatal PASMCs. Moreover, cAMP increased proliferation in neonatal but not in adult cells. Protein kinase C-stimulated adenylyl cyclase was expressed in both cell types, suggesting that insensitivity to stimulation of cAMP in adult cells was not due to decreased enzyme expression. Our data collectively indicate that protein kinase C stimulation of cAMP is a critical signal mediating proliferation of neonatal PASMCs that is absent in adult PASMCs and therefore may contribute to the unique proproliferative phenotype of these neonatal cells.

Alpha 1-adrenoceptor and purinoceptor agonists modulate Na-H antiport in single cardiac cells

1993 ◽  
Vol 264 (2) ◽  
pp. H310-H319 ◽  
Author(s):  
M. Puceat ◽  
O. Clement-Chomienne ◽  
A. Terzic ◽  
G. Vassort
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cardiac Cells ◽  
Extracellular Medium ◽  
Beta Adrenoceptor ◽  
Kinase C ◽  
Intracellular Ca ◽  
Acid Load ◽  
Ethanesulfonic Acid ◽  
Stimulation Of

We investigated the effects of an alpha 1-adrenoceptor (phenylephrine) and a purinoceptor agonist (ATP), both of which accelerate the phosphoinositide turnover, on the Na-H antiport activity of rat single cardiac cells using the pH-sensitive fluorescent indicator seminaphthorhodafluor-1 (SNARF-1). Both phenylephrine, in the presence of a beta-adrenoceptor blocker, and ATP enhanced the ability of the cell to regulate its intracellular pH (pHi) after an imposed acid load. This effect was observed in HCO3-free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) and prevented by Na-H antiport inhibitors ethylisopropylamiloride (EIPA) or amiloride. Similar results were obtained when cells were bathed in an acidic extracellular medium. Hence, the alpha 1-adrenoceptor and purinoceptor agonists activate the Na-H antiport even when it is partially inhibited by extracellular protons. To further evaluate the effects of the two neurohormones, the rate of proton efflux was estimated as a function of the magnitude of the imposed acid load. The results indicate that the agonist-induced modulation of the Na-H antiport is caused by an acceleration of its exchange activity and by a shift of its dependence on pHi toward more alkaline pH values. The agonist-mediated stimulation of the antiport was also observed in partially depolarized cells and was not dependent on intracellular Ca. Phorbol 12-myristate 13-acetate was not able to reproduce the effects of the agonists on the Na-H antiport. Conversely, the inhibitors of protein kinase C did not prevent the activation of the antiport by the neurohormones. Thus our data suggest that neither a Ca-calmodulin-dependent kinase nor protein kinase C is responsible for the alpha 1-adrenoceptor- and purinoceptor-mediated stimulation of the antiport.

Diacylglycerol and protein kinase C activate cation channels involved in myogenic tone

2002 ◽  
Vol 283 (6) ◽  
pp. H2196-H2201 ◽  
Author(s):  
Donald F. Slish ◽  
Donald G. Welsh ◽  
Joseph E. Brayden
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Transient Receptor Potential Channels ◽  
Cell Swelling ◽  
Cation Channels ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Kinase C ◽  
Intravascular Pressure

The smooth muscle cells of resistance arteries depolarize and contract when intravascular pressure is elevated. This is a central characteristic of myogenic tone, which plays an important role in regulation of blood flow in many vascular beds. Pressure-induced vascular smooth muscle depolarization depends in part on the activation of cation channels. Here, we show that activation of these smooth muscle cation channels and pressure-induced depolarization are mediated by protein kinase C in cerebral resistance arteries. Diacylglycerol, phorbol myristate acetate, and cell swelling activate a cation current that we have previously shown is mediated by transient receptor potential channels. These currents, as well as the smooth muscle cell depolarizations of intact arteries induced by diacylglycerol, phorbol ester, and elevation of intravascular pressure, are nearly eliminated by protein kinase C inhibitors. These results suggest a major mechanism of myogenic tone involves mechanotransduction through phospholipase C, diacylglycerol production, and protein kinase C activation, which increase cation channel activity. The associated depolarization activates L-type calcium channels, leading to increased intracellular calcium and vasoconstriction.

AVP-induced activation of MAP kinase in vascular smooth muscle cells is mediated through protein kinase C

1993 ◽  
Vol 265 (4) ◽  
pp. C939-C945 ◽  
Author(s):  
A. Kribben ◽  
E. D. Wieder ◽  
X. Li ◽  
V. van Putten ◽  
Y. Granot ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Map Kinase ◽  
Tyrosine Phosphorylation ◽  
Vascular Smooth Muscle Cells ◽  
Kinase C ◽  
Stimulation Of

Arginine vasopressin (AVP) has been shown to stimulate tyrosine phosphorylation and activation of p42 mitogen-activated protein (MAP) kinase (p42MAPK) in vascular smooth muscle cells (VSMC). In VSMC, AVP increases free intracellular Ca2+ concentration ([Ca2+]i) and activates protein kinase C (PKC) through activation of phospholipase C. The contribution of PKC and [Ca2+]i in p42MAPK regulation was therefore determined. Activation of PKC by phorbol 12-myristate 13-acetate (PMA) stimulated tyrosine phosphorylation and activation of p42MAPK to the same extent as AVP. Inhibition of PKC by staurosporine or downregulation of PKC by PMA pretreatment abolished AVP-induced stimulation of p42MAPK. When [Ca2+]i was elevated to the same level as with AVP, using either ionomycin (0.1 microM) or thapsigargin (0.1 microM), MAP kinase was only partially activated. Elevation of [Ca2+]i to supraphysiological levels by 1 microM ionomycin stimulated MAP kinase activity to the same extent as AVP. This effect was blocked by downregulation of PKC. The intracellular Ca2+ chelator BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid] blocked AVP-induced [Ca2+]i increase but did not affect AVP stimulation of p42MAPK. Thus AVP-induced activation of p42MAPK requires only the activation of PKC but not an increase in [Ca2+]i.

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