Ca2+/Calmodulin‐Dependent Protein Kinase II Inhibitor KN‐62 Inhibits Adrenal Medullary Chromaffin Cell Functions Independent of Its Action on the Kinase

KN-62, an inhibitor of Ca 2+ /calmodulin-dependent protein kinase II (CaM kinase II), inhibited significantly catecholamine secretion and tyrosine hydroxylase activity stimulated by acetylcholine in cultured bovine adrenal medullary cells. KN-62, however, showed an additional inhibitory effect on acetylcholine-induced 45 Ca 2+ influx, which is essential for functional responses. Carbachol-stimulated 22 Na + influx, veratridine-induced 22 Na + influx, and 56 mM K + -evoked 45 Ca 2+ influx were also attenuated by KN-62. Inhibitions by KN-62 of these ion influxes were correlated closely with those of catecholamine secretion. KN-04, which is a structural analogue of KN-62 but does not inhibit CaM kinase II activity, elicited inhibitory effects on the three kinds of stimulant-evoked ion influxes with an inhibitory potency similar to KN-62. These results suggest that KN-62 inhibits catecholamine secretion and tyrosine hydroxylase activation due to mainly its ion channel blockade on the plasma membrane rather than the inhibition of CaM kinase II activity in the cells.