β-Adrenergic modulation of calcium channels in frog ventricular heart cells

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Abstract
Adrenergic modulation of calcium channels profoundly influences cardiac function1,2, and has served as a prime example of neurohormonal regulation of voltage-gated ion channels1–7. Channel modulation and increased Ca influx2,8,9 are mediated by elevation of intracellular cyclic AMP10–17 and protein phosphorylation18,19. The molecular mechanism of the augmented membrane Ca conductance has attracted considerable interest. An increase in the density of functional channels has often been proposed20–22, but there has previously been no direct evidence. Single-channel recordings show that isoprenaline or 8-bromocyclic AMP increase the proportion of time individual channels spend open by prolonging openings and shortening the closed periods between openings2,23–25. To look for an additional contribution of changes in the number of functional channels, we applied ensemble fluctuation analysis26 to whole-cell recordings27,28 of cardiac Ca channel activity. Here we present evidence that in frog ventricular heart cells β-adrenergic stimulation increases NF, the average number of functional Ca channels per cell. We also find that isoprenaline slows the time course of both activation and inactivation, and that the enhancement of peak current decreases gradually with greater membrane depolarization.