Novel actions of ryanodine and analogues--perturbers of potassium channels.
The effects of ryanodine, 9,21-didehydroryanodine and 9,21-didehydroryanodol on two types of K(+) channel (a maxi, Ca(2+)-activated, 170pS channel (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 irreversibly induced a dose-dependent reduction of the reversal potential (V (rev)) of the currents of both channels, i.e. from 60 mV in the absence of the alkaloid to 15 mV for 10(-5) M ryanodine, measured under physiologically normal K(+) and Na(+) gradients. In both cases the change in the ionic selectivity was Ca(2+) -independent. 9,21-didehydroryanodine and 9,21-didehyroryanodol also reduced V (rev), but only to 35 mV during application of 10(-5) M of these compounds. Additionally, 9,21-didehydroryanodine reversibly diminished the conductances of the two K(+) channels. To test the hypothesis that ryanoids increase Na permeability by enlarging the K(+) channels, the channels were probed with quaternary ammonium ions during ryanoid application. When applied to the cytoplasmic face of inside-out patches excised 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-dependence for TMA block was increased for both K(+) channels, from 0.47 to 0.8 with 10(-6) M ryanodine. The effects of ryanodine on TEA and TMA block support the hypothesis that ryanodine enlarges the K(+) channels so as to facilitate permeation of partially hydrated Na(+) ions.
Vais
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Department of Life Science, The University of Nottingham, UK.
Usherwood
P N
PN
D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006110:Grasshoppers / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012433:Ryanodine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013757:Tetraethylammonium Compounds / Q000494:pharmacology
D001952:Bridged-Ring Compounds; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D013757:Tetraethylammonium Compounds; C101534:9,21-didehydroryanodol; D012433:Ryanodine; C062838:9,21-didehydroryanodine; C027917:tetramethylammonium