A neuronal beta subunit (KCNMB4) makes the large conductance, voltage- andCa2+-activated K+ channel resistant to chavybdotoxin and iberiotoxin

Large conductance voltage and Ca2+-activated K+ (MaxiK) channels couple int racellular Ca2+ with cellular excitability. They are composed of a pore-for ming alpha subunit and modulatory beta subunits. The pore blockers charybdo toxin (CTx) and iberiotoxin (IbTx), at nanomolar concentrations, have been invaluable in unraveling MaxiK channel physiological role in vertebrates. H owever in mammalian brain, CTx-insensitive MaxiK channels have been describ ed [Reinhart, P. H., Chung, S. & Levitan, I. B. (1989) Neuron 2, 1031-1041] , but their molecular basis is unknown. Here we report a human MaxiK channe l beta-subunit (beta 4), highly expressed in brain, which renders the MaxiK channel alpha-subunit resistant to nanomolar concentrations of CTx and IbT x. The resistance of MaxiK channel to toxin black, a phenotype conferred by the beta 4 extracellular loop, results from a dramatic (approximate to 1,0 00 fold) slowdown of the toxin association. However once bound, the toxin b lock is apparently irreversible. Thus. unusually high toxin concentrations and long exposure times are necessary to determine the role of "CTx/IbTx-in sensitive" MaxiK channels formed by alpha + beta 4 subunits.