B. Mlinar et Jj. Enyeart, IDENTICAL INHIBITORY MODULATION OF A-TYPE POTASSIUM CURRENTS BY DIHYDROPYRIDINE CALCIUM-CHANNEL AGONISTS AND ANTAGONISTS, Molecular pharmacology, 46(4), 1994, pp. 743-749
We have studied the interaction of dihydropyridine (DHP) Ca2+ channel
agonists and antagonists with A-type K+ channels in whole-cell patch-c
lamp recordings from bovine adrenal zona fasciculata cells. At concent
rations from 1 to 100 mu M, DHP antagonists [nimodipine and (+)-Bay K
8644] and agonists [(-)-Bay K 8644 and RS 30026] each reversibly reduc
ed A-type K+ current (I-A) amplitude and markedly accelerated the appa
rent rate of I-A inactivation. Unlike their actions on Ca2+ channels,
the effects of DHP agonists and antagonists on I-A were qualitatively
indistinguishable. Inhibition of I-A by DHPs was not accompanied by ch
anges in the voltage-dependent steady state inactivation of in Or the
kinetics of recovery subsequent to repolarization. The effects of DHPs
on peak I-A and inactivation kinetics were not use dependent. The DHP
s were much less effective in cells where fast N-type inactivation had
spontaneously diminished with time. These actions of DHPs on I-A are
in marked contrast to their voltage-dependent modulation of L-type Ca2
+ currents, indicating that fundamentally different mechanisms are inv
olved. Rather than directly occluding A-type K+ channels, the drugs ma
y enhance the voltage-independent rate of inactivation. This could occ
ur through interaction of the DHP with a site on the amino-terminal in
activation domain or the DHP binding site at the inner mouth of the ch
annel. Regardless of the mechanism involved, the identical modulation
by DHP agonists and antagonists is a distinctive feature of A-type Kchannels in adrenal zona fasciculata cells.