PROTEIN KINASE C ACTIVATES BK CHANNELS IN PULMONARY ARTERIAL SMOOTH MUSCLE VIA CGMP-DEPENDENT PROTEIN KINASE

2004 ◽  
Vol 13 (3) ◽  
pp. 43
Author(s):  
Scott A Barman ◽  
Mary L Meadows ◽  
Shu Zhu ◽  
Richard E White
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Bk Channels ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Kinase C ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

cAMP activates BKCa channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase

2003 ◽  
Vol 284 (6) ◽  
pp. L1004-L1011 ◽  
Author(s):  
Scott A. Barman ◽  
Shu Zhu ◽  
Guichan Han ◽  
Richard E. White
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Channel Activity ◽  
Dependent Protein Kinase ◽  
Arterial Smooth Muscle ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

The signal transduction mechanisms defining the role of cyclic nucleotides in the regulation of pulmonary vascular tone is currently an area of great interest. Normally, signaling mechanisms that elevate cAMP and guanosine-3′,5′-cyclic monophosphate (cGMP) maintain the pulmonary vasculature in a relaxed state. Modulation of the large-conductance, calcium- and voltage-activated potassium (BKCa) channel is important in the regulation of pulmonary arterial pressure, and inhibition (closing) of the BKCa channel has been implicated in the development of pulmonary hypertension. Accordingly, studies were done to determine the effect of cAMP-elevating agents on BKCa channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension. Forskolin (10 μM), a stimulator of adenylate cyclase and an activator of cAMP-dependent protein kinase (PKA), and 8–4-chlorophenylthio (CPT)-cAMP (100 μM), a membrane-permeable derivative of cAMP, opened BKCa channels in single FHR PASMC. Treatment of FHR PASMC with 300 nM KT5823, a selective inhibitor of cGMP-dependent protein kinase (PKG) activity inhibited the effect of both forskolin and CPT-cAMP. In contrast, blocking PKA activation with 300 nM KT5720 had no effect on forskolin or CPT-cAMP-stimulated BKCa channel activity. These results indicate that cAMP-dependent vasodilators activate BKCa channels in PASMC of FHR via PKG-dependent and PKA-independent signaling pathways, which suggests cross-activation between cyclic nucleotide-dependent protein kinases in pulmonary arterial smooth muscle and therefore, a unique signaling pathway for cAMP-induced pulmonary vasodilation.

PKC activates BKCa channels in rat pulmonary arterial smooth muscle via cGMP-dependent protein kinase

2004 ◽  
Vol 286 (6) ◽  
pp. L1275-L1281 ◽  
Author(s):  
Scott A. Barman ◽  
Shu Zhu ◽  
Richard E. White
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Channel Activity ◽  
Sprague Dawley ◽  
Dependent Protein Kinase ◽  
Pulmonary Vasoconstriction ◽  
Sprague Dawley Rat ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Normally, signaling mechanisms that activate large-conductance, calcium- and voltage-activated potassium (BKCa) channels in pulmonary vascular smooth muscle cause pulmonary vasodilatation. BKCa-channel modulation is important in the regulation of pulmonary arterial pressure, and inhibition (decrease in the opening probability) of the BKCa channel has been implicated in the development of pulmonary vasoconstriction. Protein kinase C (PKC) causes pulmonary vasoconstriction, but little is known about the effect of PKC on BKCa-channel activity in pulmonary vascular smooth muscle. Accordingly, studies were done to determine the effect of PKC on BKCa-channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMCs) of the Sprague-Dawley rat. The PKC activators phorbol myristate acetate (PMA) and thymeleatoxin opened BKCa channels in single Sprague-Dawley rat PASMC. The activator response to both PMA and thymeleatoxin on BKCa-channel activity was blocked by Gö-6983, which selectively blocks PKC-α, -δ, -γ, and -ζ, and by rottlerin, which selectively inhibits PKC-δ. In addition, the specific cyclic GMP-dependent protein kinase antagonist KT-5823 blocked the responses to PMA and thymelatoxin, whereas the specific cyclic AMP-dependent protein kinase blocker KT-5720 had no effect. In isolated pulmonary arterial vessels, both PMA and forskolin caused vasodilatation, which was inhibited by KT-5823, Gö-6983, or the BKCa-channel blocker tetraethylammonium. The results of this study indicate that activation of specific PKC isozymes increases BKCa-channel activity in Sprague-Dawley rat PASMC via cyclic GMP-dependent protein kinase, which suggests a unique signaling mechanism for vasodilatation.

Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms

1991 ◽  
Vol 69 (3) ◽  
pp. 383-388 ◽  
Author(s):  
N. Jin ◽  
C. S. Packer ◽  
R. A. Rhoades
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cellular Mechanisms ◽  
Kinase C ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Oxidase Reaction

Reactive oxygen species (at least relatively high doses) cause contraction of pulmonary arterial smooth muscle. The objective of the present study was to elucidate the possible cellular mechanisms involved in reactive oxygen-mediated contraction. Isolated arterial rings from Sprague–Dawley rats were placed in tissue baths containing Earle's balanced salt solution. The maximum active force production (Po) in response to 80 mM KCl was obtained. All other responses were normalized as percentages of Po for comparative purposes. Exposure to reactive oxygen (generated from either the xanthine oxidase reaction (XO) or the glucose oxidase reaction) resulted in pulmonary arterial muscle developing mean active tension of 17.1 ± 3.0% Po. This contraction was independent of extracellular calcium, since it was not affected by verapamil (a calcium channel blocker) or by placement of the arterial muscle in calcium-free media. Phentolamine (an α1-receptor blocker) and propranolol (a β-receptor blocker) did not diminish the response to XO. Ryanodine (a SR calcium release inhibitor), while reducing the response to norepinephrine, did not affect the response to XO. However, H-7 (an inhibitor of protein kinase C) decreased the XO-mediated contraction by 49%. These results indicate that while Ca2+ may not be involved as a second messenger, protein kinase C activity appears to play a role in the transduction pathway of reactive oxygen species mediated contraction of pulmonary arterial smooth muscle.Key words: muscle calcium, α1-receptor, ryanodine, protein kinase C, vascular smooth muscle, oxygen radicals, verapamil.

Protein kinase C inhibits BKCa channel activity in pulmonary arterial smooth muscle

2004 ◽  
Vol 286 (1) ◽  
pp. L149-L155 ◽  
Author(s):  
Scott A. Barman ◽  
Shu Zhu ◽  
Richard E. White
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Channel Activity ◽  
Arterial Smooth Muscle ◽  
Pulmonary Vasoconstriction ◽  
Kinase C ◽  
Pkc Isozymes ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Signaling mechanisms that elevate cyclic AMP (cAMP) activate large-conductance, calcium- and voltage-activated potassium (BKCa) channels in pulmonary vascular smooth muscle and cause pulmonary vasodilatation. BKCa channel modulation is important in the regulation of pulmonary arterial pressure, and inhibition (closing) of the BKCa channel has been implicated in the development of pulmonary vasoconstriction. Protein kinase C (PKC) causes pulmonary vasoconstriction, but little is known about the effect of PKC on BKCa channel activity. Accordingly, studies were done to determine the effect of PKC activation on cAMP-induced BKCa channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension. Forskolin (10 μM), a stimulator of adenylate cyclase and an activator of cAMP, opened BKCa channels in single FHR PASMC, which were blocked by the PKC activators phorbol 12-myristate 13-acetate (100 nM) and thymeleatoxin (100 nM). The inhibitory response by thymeleatoxin on forskolin-induced BKCa channel activity was blocked by Gö-6983, which selectively blocks the α, β, δ, γ, and ζ PKC isozymes, and Gö-6976, which selectively inhibits PKC-α, PKC-β, and PKC-μ, but not by rottlerin, which selectively inhibits PKC-δ. Collectively, these results indicate that activation of specific PKC isozymes inhibits cAMP-induced activation of the BKCa channel in pulmonary arterial smooth muscle, which suggests a unique signaling pathway to modulate BKCa channels and subsequently cAMP-induced pulmonary vasodilatation.

scholarly journals Activation of cGMP-dependent Protein Kinase by Protein Kinase C

2003 ◽  
Vol 278 (19) ◽  
pp. 16706-16712 ◽  
Author(s):  
Yali Hou ◽  
Judith Lascola ◽  
Nickolai O. Dulin ◽  
Richard D. Ye ◽  
Darren D. Browning
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Kinase C ◽  
Dependent Protein
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