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Cardiovascular Research 2000 48(3):367-374; doi:10.1016/S0008-6363(00)00194-2
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Protein kinase G reverses all isoproterenol induced changes of cardiac single L-type calcium channel gating

Gunnar Klein, Helmut Drexler and Frank Schröder*

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany

* Corresponding author. Tel.: +49-511-532-3841; fax: +49-511-532-5412 schroeder.f{at}mh-hannover.de

Objective: cGMP reduces the effect of β-adrenoceptor agonists on cardiac L-type calcium current by protein kinase G activation. Stimulation of β-adrenoceptors increases protein kinase A dependent phosphorylation of L-type calcium channels via cAMP. At the single channel level, protein kinase A dependent phosphorylation increases both availability and open probability. The present study investigates how cGMP antagonises protein kinase A induced changes of single L-type calcium channel gating. Methods: Single L-type calcium channels were recorded in the cell attached configuration of the patch clamp technique in isolated mouse ventricular myocytes. Results: The β-adrenoceptor agonist isoproterenol (10–6 M) enhanced single channel peak average current by increasing availability and open probability and decreasing the time constant of long close times. 8-Br-cGMP (10–3 M) completely reversed these effects. The phosphatase inhibitor okadaic acid (10–6 M) did not influence the effect of 8-Br-cGMP. The protein kinase G inhibitor Rp-8Br-PET-cGMPS (10–7 M) abated the effect of 8-Br-cGMP. Activation of protein kinase A by the hydrolysis-resistant cAMP derivative 8-Br-cAMP (10–3 M) enhanced L-type calcium channel activity like isoproterenol and its effect was also reversed by 8-Br-cGMP. Conclusion: 8-Br cGMP diminishes β-adrenoceptor activation of L-type calcium channels via protein kinase G. It interacts with the β-adrenoceptor signaling pathway distal of adenylyl cyclase. Our observations suggest that protein kinase G interacts either with protein kinase A or directly with the L-type calcium channel.

KEYWORDS Signal transduction; Protein kinases; Adrenergic (ant)agonists; Ca-channel; Myocytes; Single channel currents


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