© 2000 American Heart Association, Inc.
Cellular Biology |
cAMP-Dependent Vasodilators Cross-Activate the cGMP-Dependent Protein Kinase to Stimulate BKCa Channel Activity in Coronary Artery Smooth Muscle Cells
From the Department of Pharmacology and Toxicology (R.E.W., G.H., G.O.C.), Medical College of Georgia, Augusta, Ga; Department of Physiology and Biophysics (J.P.K.), Wright State University School of Medicine, Dayton, Ohio; and School of Pharmacy (A.M.E.-M.), Kuwait University.
Correspondence to Richard E. White, PhD, Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th St, Room CB-3730, August, GA 30912-2300. E-mail rwhite{at}mail.mcg.edu
Abstract—cAMP-dependent vasodilators are used to treat a variety of cardiovascular disorders; however, the signal transduction pathways and effector mechanisms stimulated by these agents are not fully understood. In the present study we demonstrate that cAMP-stimulating agents enhance the activity of the large-conductance, calcium-activated potassium (BKCa) channel in single myocytes from coronary arteries by "cross-activation" of the cGMP-dependent protein kinase (protein kinase G, PKG). Single-channel patch-clamp data revealed that 10 µmol/L isoproterenol, forskolin, or dopamine opens BKCa channels in coronary myocytes and that this effect is attenuated by inhibitors of PKG (KT5823; Rp-8-pCPT-cGMPS), but not by inhibiting the cAMP-dependent protein kinase (protein kinase A, PKA). In addition, a membrane-permeable analog, CPT-cAMP, also opened BKCa channels in these myocytes, and this effect was reversed by KT5823. Direct biochemical measurement confirmed that dopamine or forskolin stimulates PKG activity in coronary arteries but does not elevate cGMP. Finally, the stimulatory effect of cAMP on BKCa channels was reconstituted in a cell-free, inside-out patch by addition of purified PKG activated by either cGMP or cAMP. In contrast, channel gating was unaffected by exposure to the purified catalytic subunit of PKA. In summary, findings from on-cell and cell-free patch-clamp experiments provide direct evidence that cAMP-dependent vasodilators open BKCa channels in coronary myocytes by cross-activation of PKG (but not via PKA). Biochemical assay confirmed this cross-activation mechanism of cAMP action in these arteries. This signaling pathway is a novel mechanism for regulation of potassium channel activity in vascular smooth muscle and other cells.
Key Words: cAMP • protein kinase G • BKCa channel • coronary • cross-activation
This article has been cited by other articles:
 |
|
 |
|
  S. Zhu, D. D. Browning, R. E. White, D. Fulton, and S. A. Barman Mutation of protein kinase C phosphorylation site S1076 on {alpha}-subunits affects BKCa channel activity in HEK-293 cells Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L758 - L766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Atkins, B. Irey, N. Xiang, and F. C. Brosius 3rd. A rapid, PPAR-{gamma}-dependent effect of pioglitazone on the phosphorylation of MYPT Am J Physiol Cell Physiol, May 1, 2009; 296(5): C1151 - C1161. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hou, S. H. Heinemann, and T. Hoshi Modulation of BKCa Channel Gating by Endogenous Signaling Molecules Physiology, February 1, 2009; 24(1): 26 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Duncker and R. J. Bache Regulation of Coronary Blood Flow During Exercise Physiol Rev, July 1, 2008; 88(3): 1009 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Shu Zhu, R. E. White, and S. A. Barman Original Research: Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle Therapeutic Advances in Respiratory Disease, June 1, 2008; 2(3): 119 - 127. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Zeng, I. Armando, Y. Luo, G. M. Eisner, R. A. Felder, and P. A. Jose Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H551 - H569. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Luykenaar and D. G. Welsh Activators of the PKA and PKG pathways attenuate RhoA-mediated suppression of the KDR current in cerebral arteries Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2654 - H2663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Merkus, O. Sorop, B. Houweling, B. A. Hoogteijling, and D. J. Duncker KCa+ channels contribute to exercise-induced coronary vasodilation in swine Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2090 - H2097. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Park, J. H. Lee, C. D. Kim, W. S. Lee, W. S. Park, J. Han, Y.-G. Kwak, K. Y. Kim, and K. W. Hong Cilostazol Suppresses Superoxide Production and Expression of Adhesion Molecules in Human Endothelial Cells via Mediation of cAMP-Dependent Protein Kinase-Mediated Maxi-K Channel Activation J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1238 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ay, A. Iyanoye, G. C. Sieck, Y. S. Prakash, and C. M. Pabelick Cyclic nucleotide regulation of store-operated Ca2+ influx in airway smooth muscle Am J Physiol Lung Cell Mol Physiol, February 1, 2006; 290(2): L278 - L283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhou, L. Liu, and D. Hu Involvement of BKCa {alpha} subunit tyrosine phosphorylation in vascular hyporesponsiveness of superior mesenteric artery following hemorrhagic shock in rats Cardiovasc Res, November 1, 2005; 68(2): 327 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Doheny, C. M. Lynch, T. J. Smith, and J. J. Morrison Functional Coupling of {beta}3-Adrenoceptors and Large Conductance Calcium-Activated Potassium Channels in Human Uterine Myocytes J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5786 - 5796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Linder, L. P. McCluskey, K. R. Cole III, K. M. Lanning, and R. C. Webb Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 9 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Leffler, A. L. Fedinec, H. Parfenova, and J. H. Jaggar Permissive contributions of NO and prostacyclin in CO-induced cerebrovascular dilation in piglets Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H432 - H438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. William, J. Vien, E. Hamilton, A. Garcia, H. Bundgaard, R. J Clarke, and H. H Rasmussen The nitric oxide donor sodium nitroprusside stimulates the Na+-K+ pump in isolated rabbit cardiac myocytes J. Physiol., June 15, 2005; 565(3): 815 - 825. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lee, G. T. Oh, S. Y. Park, J.-H. Choi, J.-G. Park, C. D. Kim, W. S. Lee, B. Y. Rhim, Y. W. Shin, and K. W. Hong Cilostazol Reduces Atherosclerosis by Inhibition of Superoxide and Tumor Necrosis Factor-{alpha} Formation in Low-Density Lipoprotein Receptor-Null Mice Fed High Cholesterol J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 502 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Matsumoto, K. Wakabayashi, T. Kobayashi, and K. Kamata Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1064 - H1071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Barman, S. Zhu, and R. E. White PKC activates BKCa channels in rat pulmonary arterial smooth muscle via cGMP-dependent protein kinase Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1275 - L1281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Barman, S. Zhu, and R. E. White Protein kinase C inhibits BKCa channel activity in pulmonary arterial smooth muscle Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L149 - L155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kim, J. Chung, E. Kim, and J. Han Changes in the Ca2+-Activated K+ Channels of the Coronary Artery During Left Ventricular Hypertrophy Circ. Res., September 19, 2003; 93(6): 541 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Aizawa, H. Wei, J. M. Miano, J.-i. Abe, B. C. Berk, and C. Yan Role of Phosphodiesterase 3 in NO/cGMP-Mediated Antiinflammatory Effects in Vascular Smooth Muscle Cells Circ. Res., September 5, 2003; 93(5): 406 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Lin, D. A. Hessinger, W. J. Pearce, and L. D. Longo Developmental differences in Ca2+-activated K+ channel activity in ovine basilar artery Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H701 - H709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Barman, S. Zhu, G. Han, and R. E. White cAMP activates BKCa channels in pulmonary arterial smooth muscle via cGMP-dependent protein kinase Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L1004 - L1011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Kim, J. Han, and E. Kim Effects of prostaglandin F2alpha on membrane currents in rabbit middle cerebral arterial smooth muscle cells Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H1018 - H1027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Babaei and D. J Stewart Overexpression of endothelial NO synthase induces angiogenesis in a co-culture model Cardiovasc Res, July 1, 2002; 55(1): 190 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E White, G. Han, M. Maunz, C. Dimitropoulou, A. M El-Mowafy, R. S Barlow, J. D Catravas, C. Snead, G. O Carrier, S. Zhu, et al. Endothelium-independent effect of estrogen on Ca2+-activated K+ channels in human coronary artery smooth muscle cells Cardiovasc Res, February 15, 2002; 53(3): 650 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Keef, J. R. Hume, and J. Zhong Regulation of cardiac and smooth muscle Ca2+ channels (CaV1.2a,b) by protein kinases Am J Physiol Cell Physiol, December 1, 2001; 281(6): C1743 - C1756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P. Deenadayalu, R. E. White, J. N. Stallone, X. Gao, and A. J. Garcia Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1720 - H1727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Dimitropoulou, R. E. White, L. Fuchs, H. Zhang, J. D. Catravas, and G. O. Carrier Angiotensin II Relaxes Microvessels Via the AT2 Receptor and Ca2+-Activated K+ (BKCa) Channels Hypertension, February 1, 2001; 37(2): 301 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Swayze and A. P. Braun A Catalytically Inactive Mutant of Type I cGMP-dependent Protein Kinase Prevents Enhancement of Large Conductance, Calcium-sensitive K+ Channels by Sodium Nitroprusside and cGMP J. Biol. Chem., June 1, 2001; 276(23): 19729 - 19737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. M. Dick and K. M. Sanders (Xeno)estrogen Sensitivity of Smooth Muscle BK Channels Conferred by the Regulatory beta 1 Subunit. A STUDY OF beta 1 KNOCKOUT MICE J. Biol. Chem., November 21, 2001; 276(48): 44835 - 44840. [Abstract] [Full Text] [PDF]
|
|