Mechanisms of calcium channel modulation by beta-adrenergic agents and dihydropyridine calcium agonists

Abstract

Cardiac calcium channel activity is markedly increased by beta-adrenergic agents or calcium agonists such as Bay K 8644. The molecular mechanisms underlying these important modulatory effects have been studied with patch clamp techniques by several groups. This paper presents new experiments and reviews published evidence from fluctuation analysis of whole cell calcium current and unitary recordings of single calcium channel activity. Two different factors underlie the enhancement of calcium channel activity seen with beta-stimulation or cyclic AMP: (1) increased availability of calcium channels, expressed in whole cell recordings as an increase in the number of functional channels and in single channel recordings as an increase in the proportion of non-blank sweeps. (2) changes in opening probability, due to alteration of the fast kinetics of channel opening and closing. Both factors contribute to the beta-adrenergic enhancement in frog, rat, and guinea-pig ventricular cells although their quantitative importance is somewhat variable. Unlike beta-adrenergic agents, calcium agonists such as Bay K 8644 promote a mode of channel gating that is characterized by long openings and short closings, seen only rarely in control or with beta-stimulation.