Stimulation of cardiac L-type calcium channels by extracellular ATP

Abstract

The co-release of ATP with norepinephrine from sympathetic nerve terminals in the heart may augment adrenergic stimulation of cardiac Ca2+ channel activity. To test for a possible direct effect of extracellular ATP on L-type Ca2+ channels, single channels were reconstituted from porcine sarcolemma into planar lipid bilayers so that intracellular signaling pathways could be controlled. Extracellular ATP (2–100 μM) increased the open probability of the reconstituted channels, with a maximal increase of ∼2.6-fold and an EC50 of 3.9 μM. The increase in open probability was due to an increase in channel availability and a decrease in channel inactivation rate. Other nucleotides displayed a rank order of effectiveness of ATP > α,β-methylene-ATP > 2-methylthio-ATP > UTP > adenosine 5′- O-(3-thiotriphosphate) >> ADP; adenosine had no effect. Several antagonists of P2 receptors had no impact on the ATP-dependent increase in open probability, indicating that receptor activation was not required. These results suggest that extracellular ATP and other nucleotides can stimulate the activity of cardiac L-type Ca2+ channels via a direct interaction with the channels.