ELECTROPHYSIOLOGICAL EFFECTS OF CALCITONIN GENE-RELATED PEPTIDE IN BULLFROG AND GUINEA-PIG ATRIAL MYOCYTES

1. Electrophysiological effects of calcitonin gene-related peptide (CGRP) on action potentials and corresponding transmembrane currents in single myocytes from bull-frog and guinea-pig atria were studied using a whole-cell voltage-clamp method. 2. CGRP at relatively low concentrations increased the height of the action potential plateau in a dose-dependent manner in both bull-frog and guinea-pig myocytes. In addition, in bull-frog cells CGRP accelerated the early phase of repolarization, thus shortening the overall duration of the action potential. In contrast, in guinea-pig myocytes CGRP prolonged the action potential duration at all concentrations that were studied. 3. Voltage-clamp measurements demonstrated that CGRP increased transmembrane calcium current (I(Ca)) in guinea-pig myocytes without a significant change in its voltage dependence. The ED50 value for this effect on I(Ca) was 1.28 +/- 0.55 x 10(-8) M (n = 4). The time course of the inactivation of I(Ca) was not affected by CGRP. 4. CGRP increased the delayed rectifier K+ current (I(K)) at relatively low concentrations in bull-frog atria, whereas relatively high concentrations were needed to increase I(K) in guinea-pig myocytes. This effect was observed even after complete inhibition of I(Ca). 5. CGRP had no significant effect on the inwardly rectifying background K+ current, I(K1), even at very high concentrations. 6. Comparison of the time course of I(Ca) augmentation in bull-frog and guinea-pig myocytes revealed an important difference in the effect of CGRP in these two types of cells. CGRP at maximal concentrations increased I(Ca) transiently in bull-frog myocytes, whereas this response was sustained in guinea-pig myocytes. Isoprenaline (Iso) induced sustained increase in I(Ca) in both species. When I(Ca) was fully activated by Iso, CGRP at high concentrations strongly inhibited I(Ca) in the bull-frog, whereas it had little effect on I(Ca) in guinea-pig myocytes. 7. Intracellular application of GTP-gamma-S (guanosine 5'-O-(3-thiotriphosphate), 10(-4) M) greatly potentiated the CGRP effect on I(Ca); in contrast, GDP-beta-S (guanosine 5'-O-(2-thiodiphosphate), 2 x 10(-3) M) partially inhibited the CGRP-induced augmentation of I(Ca). Taken together, these results indicate that the stimulation of I(Ca) by CGRP is mediated by a GTP-binding protein. 8. The observed dose-dependent changes in I(Ca) and I(K) in bull-frog and guinea-pig myocytes can explain the different patterns of CGRP-induced changes in action potential shape in these two myocyte preparations.