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Cardiovascular Research 2003 60(2):268-277; doi:10.1016/S0008-6363(03)00546-7
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Single L-type Ca2+ channel regulation by cGMP-dependent protein kinase type I in adult cardiomyocytes from PKG I transgenic mice

Frank Schröder*,a, Gunnar Kleina, Beate Fiedlera, Michaela Basteina, Nicole Schnassea, Anja Hillmera, Sandra Amesa, Stepan Gambaryanb, Helmut Drexlera, Ulrich Walterb, Suzanne M Lohmannb and Kai C Wollerta

aDepartment of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
bInstitute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Germany

*Corresponding author. Abt. Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Tel.: +49-511-532-3007; fax: +49-511-532-5412. Email address: schroeder.f{at}mh-hannover.de

Objective: Calcium entry via the L-type Ca2+ channel (LTCC) is crucial for excitation–contraction (EC) coupling and activation of Ca2+-dependent signal transduction pathways in cardiac myocytes. Both nitric oxide (NO), signaling via cGMP, and acetylcholine, signaling via the muscarinic receptor, have been identified as negative regulators of β-adrenoreceptor-stimulated LTCC activity in cardiac myocytes. Methods: To examine the potential role of cGMP-dependent protein kinase type I (PKG I) in the inhibitory effects of NO/cGMP and the muscarinic receptor on LTCC activity, we generated transgenic (TG) mice overexpressing PKG I selectively in cardiac myocytes under the control of the {alpha}-myocin heavy chain promoter. Single LTCC-gating properties were assessed in isolated ventricular myocytes from adult wild-type (WT) and PKG I transgenic (TG) mice. Results: Basal LTCC activity (peak average current, mean open probability, mean availability) was significantly decreased by the nitric oxide donor DEA-NO (0.1 µmol/l) and the cGMP-analog 8-Br-cGMP (1 mmol/l) in TG but not in WT cardiac myocytes. Conversely, muscarinic (carbachol, 1 µmol/l) stimulation had no significant effect on basal LTCC activity in either WT or TG cardiac myocytes. β-Adrenergic stimulation with isoproterenol (1 µmol/l) increases single LTCC activity in WT and TG cardiac myocytes to the same extent. The inhibitory effects of DEA-NO and 8-Br-cGMP on isoproterenol activation of the LTCC current were significantly enhanced in TG as compared to WT cardiac myocytes. By contrast, carbachol inhibition of isoproterenol-stimulated single LTCC activity was not enhanced in TG cardiac myocytes. Conclusion: Transgenic overexpression of PKG I augments NO/cGMP inhibition but not muscarinic inhibition of single LTCC activity, indicating that PKG I is a downstream target for NO/cGMP, but not the muscarinic receptor in adult cardiac myocytes.

KEYWORDS L-type Ca2+ channel; Nitric oxide; cGMP; Muscarinic receptor; cGMP-dependent protein kinase type I

Time for primary review 23 days


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