Multiple kinetic effects of beta-adrenergic stimulation on single cardiac L-type Ca channels

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Abstract
During beta-adrenergic stimulation, several different mechanisms are known to modulate single cardiac L-type Ca channels, such as an increase in the proportion of nonblank sweeps (availability), graded changes in open and closed time constants, and potentiation of "mode 2" gating. To clarify the interrelationships of the above mechanisms in terms of "molecular modulation," we reevaluated the adenosine 3',5'-cyclic monophosphate-dependent increase in single cardiac Ca channel activity under conditions where all of the proposed mechanisms could take place. We observed considerable variations in the kinetic properties of basal channel activity among individual patches, presumably due to the diversity of intracellular metabolic conditions of individual myocytes. This made the contribution by each mechanism as described above variable from one patch to another. Increases in open probability during nonblank sweeps (associated with increased open time constant and/or promotion of mode 2 gating) were observed in patches were the increased nonblank rate was already established in the control state. In contrast with the report by D. T. Yue, S. Herzig, and E. Marban (Proc. Natl. Acad. Sci. USA 87: 753-757, 1990), graded changes in the open time constant could take place independently from the potentiation of mode 2 gating behavior. Our results suggest that the enhancement of cardiac L-type Ca channels during beta-stimulation involves multiple functional modulatory sites, which might be phosphorylated independently.