This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hool, L. C. Search for Related Content PubMed PubMed Citation Articles by Hool, L. C. Related Collections Cell signalling/signal transduction Ion channels/membrane transport Oxidant stress

(Circulation Research. 2000;87:1164.)
© 2000 American Heart Association, Inc.

Cellular Biology

Hypoxia Increases the Sensitivity of the L-Type Ca²⁺ Current to ß-Adrenergic Receptor Stimulation via a C2 Region–Containing Protein Kinase C Isoform

Livia C. Hool

From the Department of Physiology, The University of Western Australia, Nedlands, Western Australia.

Correspondence to Dr Livia C. Hool, Department of Physiology, The University of Western Australia, Hackett Drive, Nedlands, WA, 6907, Australia. E-mail lhool{at}cyllene.uwa.edu.au

Abstract—The effects of hypoxia on the L-type Ca²⁺ current (I_Ca-L) in the absence and presence of the ß-adrenergic receptor agonist isoproterenol (Iso) were examined. Exposing guinea pig ventricular myocytes to hypoxia alone resulted in a reversible inhibition of basal I_Ca-L. When cells were exposed to Iso in the presence of hypoxia, the K_0.5 for activation of I_Ca-L by Iso was significantly decreased from 5.3±0.7 to 1.6±0.1 nmol/L. The membrane-impermeant thiol-specific oxidizing compound 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) attenuated the inhibition of basal I_Ca-L by hypoxia 81.3±9.4% but had no effect on the increase in sensitivity of I_Ca-L to Iso. In addition, DTT mimicked the effects of hypoxia on basal I_Ca-L and the increase in sensitivity to Iso. Neither the inhibitors of guanylate cyclase LY-83583 or methylene blue nor the NO synthase inhibitor N^G-monomethyl-L-arginine monoacetate had any effect on the basal inhibition of I_Ca-L or the decrease in K_0.5 for activation of I_Ca-L by Iso during hypoxia. However, the protein kinase C (PKC) inhibitors bisindolylmaleimide I and Gö 7874 significantly attenuated the increase in sensitivity of I_Ca-L to Iso. More specifically, the response was attenuated when cells were dialyzed with a peptide inhibitor of the C2 region–containing classical PKC isoforms. The same effect was not observed with the PKC peptide inhibitor. These results suggest that hypoxia regulates I_Ca-L through the following 2 distinct mechanisms: direct inhibition of basal I_Ca-L and an indirect effect on the sensitivity of the channel to ß-adrenergic receptor stimulation that is mediated through a classical PKC isoform.

Key Words: hypoxia • ß-adrenergic receptor • L-type Ca²⁺ channels • nitric oxide • protein kinase C

This article has been cited by other articles:

				A. S. Barth and G. F. Tomaselli Cardiac Metabolism and Arrhythmias Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 327 - 335. [Full Text] [PDF]

				H. M. Viola, P. G. Arthur, and L. C. Hool Transient Exposure to Hydrogen Peroxide Causes an Increase in Mitochondria-Derived Superoxide As a Result of Sustained Alteration in L-Type Ca2+ Channel Function in the Absence of Apoptosis in Ventricular Myocytes Circ. Res., April 13, 2007; 100(7): 1036 - 1044. [Abstract] [Full Text] [PDF]

				S. Pouvreau and V. Jacquemond Nitric oxide synthase inhibition affects sarcoplasmic reticulum Ca2+ release in skeletal muscle fibres from mouse J. Physiol., September 15, 2005; 567(3): 815 - 828. [Abstract] [Full Text] [PDF]

				R. T. Mallet Hypoxic modulation of cardiac L-type Ca2+ current: Interaction of reactive oxygen species and {beta}-adrenergic signaling Cardiovasc Res, September 1, 2005; 67(4): 578 - 580. [Full Text] [PDF]

				L. C. Hool, C. A. Di Maria, H. M. Viola, and P. G. Arthur Role of NAD(P)H oxidase in the regulation of cardiac L-type Ca2+ channel function during acute hypoxia Cardiovasc Res, September 1, 2005; 67(4): 624 - 635. [Abstract] [Full Text] [PDF]

				G. H. Fukumoto, S. T. Lamp, C. Motter, J. H.B. Bridge, A. Garfinkel, and J. I. Goldhaber Metabolic Inhibition Alters Subcellular Calcium Release Patterns in Rat Ventricular Myocytes: Implications for Defective Excitation-Contraction Coupling During Cardiac Ischemia and Failure Circ. Res., March 18, 2005; 96(5): 551 - 557. [Abstract] [Full Text] [PDF]

				L. C. Hool Differential regulation of the slow and rapid components of guinea-pig cardiac delayed rectifier K+ channels by hypoxia J. Physiol., February 1, 2004; 554(3): 743 - 754. [Abstract] [Full Text] [PDF]

				K. B. Walsh and Q. Cheng Intracellular Ca2+ regulates responsiveness of cardiac L-type Ca2+ current to protein kinase A: role of calmodulin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H186 - H194. [Abstract] [Full Text] [PDF]

				L. C. Hool and P. G. Arthur Decreasing Cellular Hydrogen Peroxide With Catalase Mimics the Effects of Hypoxia on the Sensitivity of the L-Type Ca2+ Channel to {beta}-Adrenergic Receptor Stimulation in Cardiac Myocytes Circ. Res., October 4, 2002; 91(7): 601 - 609. [Abstract] [Full Text] [PDF]

				L. C. Hool Hypoxia Alters the Sensitivity of the L-Type Ca2+ Channel to {alpha}-Adrenergic Receptor Stimulation in the Presence of {beta}-Adrenergic Receptor Stimulation Circ. Res., May 25, 2001; 88(10): 1036 - 1043. [Abstract] [Full Text] [PDF]