D. Rampe et al., VERAPAMIL BLOCKS A RAPIDLY ACTIVATING DELAYED RECTIFIER K+ CHANNEL CLONED FROM HUMAN HEART, Molecular pharmacology, 44(3), 1993, pp. 642-648
Verapamil is an antagonist of L-type Ca2+ channels, and part of its bi
nding site is located in the sixth transmembrane segment (S6) in the f
ourth repeat of the protein. Verapamil also blocks K+ channels, which
are members of the same supergene family as Ca2+ channels. We examined
the effects of verapamil on a rapidly activating delayed rectifier K channel (designated fHK) cloned from human heart. Verapamil inhibited
Rb-86+ efflux from fHK-transfected human embryonic kidney cells with
an EC50 of 4.5 x 10(-5) m. Whole-cell patch-clamp experiments revealed
that verapamil induced a rapid component of fHK current inactivation
but was without effect on activation. The effect was concentration and
voltage dependent and was attributed to open channel blockade. The ap
parent association and dissociation rate constants measured at +50 mV
were about 1.65 x 10(5) m-1 sec-1 and 3.48 sec-1, respectively. S6 of
fHK has significant homology to that portion of the verapamil binding
site identified in Ca2+ channels, and S6 is thought to form part of th
e inner mouth of K+ channel pores. The data support a role for verapam
il as a blocker of the inner pore of voltage-dependent K+ channels in
human myocardium.