CA2+ CURRENT IS REGULATED BY CYCLIC GMP-DEPENDENT PROTEIN-KINASE IN MAMMALIAN CARDIAC MYOCYTES

Regulation of cardiac contraction by neurotransmitters and hormones is often correlated with regulation of the L-type Ca2+ -channel current (I(Ca)) through the opposite actions of two second messengers, cyclic AMP and cyclic GMP. While cyclic AMP stimulation of I(Ca) is mediated by the activation of cyclic AMP-dependent protein kinase, inhibition of I(Ca) by cyclic GMP in frog heart is largely mediated by activation of cyclic AMP phosphodiesterase. The present patch-clamp study reveals that, in rat ventricular cells, cyclic GMP can also regulate I(Ca) via activation of endogenous cyclic GMP-dependent protein kinase (cGMP-PK). Indeed, the effect of cyclic GMP on I(Ca) was mimicked by intracellular perfusion with the proteolytic active fragment of purified cGMP-PK. Moreover, cGMP-PK immunoreactivity was detected in pure rat ventricular myocytes by using a specific polyclonal antibody. These results demonstrate a dual mechanism for the inhibitory action of cyclic GMP in heart, as well as a physiological role for cGMP-PK in the control of mammalian heart function.