Interactions of monovalent cations with sodium channels in squid axon. II. Modification of pharmacological inactivation gating.
The time-, frequency-, and voltage-dependent blocking actions of several cationic drug molecules on open Na channels were investigated in voltage-clamped, internally perfused squid giant axons. The relative potencies and time courses of block by the agents (pancuronium [PC], octylguanidinium [C8G], QX-314, and 9-aminoacridine [9-AA]) were compared in different intracellular ionic solutions; specifically, the influences of internal Cs, tetramethylammonium (TMA), and Na ions on block were examined. TMA+ was found to inhibit the steady state block of open Na channels by all of the compounds. The time-dependent, inactivation-like decay of Na currents in pronase-treated axons perfused with either PC, 9-AA, or C8G was retarded by internal TMA+. The apparent dissociation constants (at zero voltage) for interaction between PC and 9-AA with their binding sites were increased when TMA+ was substituted for Cs+ in the internal solution. The steepness of the voltage dependence of 9-AA or PC block found with internal Cs+ solutions was greatly reduced by TMA+, resulting in estimates for the fractional electrical distance of the 9-AA binding site of 0.56 and 0.22 in Cs+ and TMA+, respectively. This change may reflect a shift from predominantly 9-AA block in the presence of Cs+ to predominantly TMA+ block. The depth, but not the rate, of frequency-dependent block by QX-314 and 9-AA is reduced by internal TMA+. In addition, recovery from frequency-dependent block is not altered. Elevation of internal Na produces effects on 9-AA block qualitatively similar to those seen with TMA+. The results are consistent with a scheme in which the open channel blocking drugs, TMA (and Na) ions, and the inactivation gate all compete for a site or for access to a site in the channel from the intracellular surface. In addition, TMA ions decrease the apparent blocking rates of other drugs in a manner analogous to their inhibition of the inactivation process. Multiple occupancy of Na channels and mutual exclusion of drug molecules may play a role in the complex gating behaviors seen under these conditions.
Yeh
J Z
JZ
Oxford
G S
GS
D000585:Aminacrine / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000378:metabolism*; D002414:Cations, Monovalent / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology*; D049832:Decapodiformes; D004594:Electrophysiology; D006146:Guanidines / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D010197:Pancuronium / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012964:Sodium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
D002414:Cations, Monovalent; D006146:Guanidines; D007473:Ion Channels; D000644:Quaternary Ammonium Compounds; D002586:Cesium; C015403:octylguanidine; D000585:Aminacrine; D012964:Sodium; C027917:tetramethylammonium; D010197:Pancuronium