NOVEL ACTIONS OF RYANODINE AND ANALOGS - PERTURBERS OF POTASSIUM CHANNELS

The effects of ryanodine, 9,21-didehydroryanodine and 9,21-didehydrory anodol on two types of K+ channel (a maxi, Ca2+-activated, 170 pS chan nel (BK channel) and an inward rectifier, stretch-sensitive channel of 35 pS conductance (IK channel) found in the plasma membrane of locust skeletal muscle have been investigated. 10-9 M-10(-5) M ryanodine irr eversibly induced a dose-dependent reduction of the reversal potential (V-rev) of the currents of both channels, i.e. from similar to 60 mV in the absence of the alkaloid to similar to 15 mV for 10(-5) M ryanod ine, measured under physiologically normal K+ and Na+ gradients. In bo th cases the change in the ionic selectivity was Ca2+-independent. 9,2 1-didehydroryanodine and 9,21-didehyroryanodol also reduced V-rev, but only to similar to 35 mV during application of 10(-5) M of these comp ounds. Additionally, 9,21-didehydroryanodine reversibly diminished the conductances of the two K+ channels. To test the hypothesis that ryan oids increase Na+ permeability by enlarging the K+ channels, the chann els were probed with quaternary ammonium ions during ryanoid applicati on, When applied to the cytoplasmic face of inside-out patches exised from locust muscle membrane, TEA blocked the K+ channels in a voltage- dependent fashion. The dissociation constant (K-d(0)) for TEA block of the IK channel was reduced from 44 mM to 1 mM by 10(-7) M ryanodine, but the voltage-dependence of the block was unaffected. Qualitatively similar data were obtained for the BK channel. Ryanodine had no effect on the K-d for cytoplasmically-applied TMA. However, the voltage-depe ndence for TMA block was increased for both K+ channels, from 0.47 to similar to 0.8 with 10(-6) M ryanodine. The effects of ryanodine on TE A and TMA block support the hypothesis that ryanodine enlarges the Kchannels so as to facilitate permeation of partially hydrated Na+ ions .