scholarly journals Overactivation of Ca 2+ /Calmodulin‐Dependent Protein Kinase IV and IIδ Contributes to Enhancing Pulmonary Arterial Smooth Muscle Cell Proliferation in Patients with Idiopathic Pulmonary Arterial Hypertension

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Shane Geary Carr ◽  
Shanshan Song ◽  
Kang Wu ◽  
Ziyi Wang ◽  
Jason X.‐J. Yuan
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Protein Kinase ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Arterial Smooth Muscle Cell ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

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.

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.

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