DUAL EFFECTS OF INTERNAL NORMAL-ALKYLTRIMETHYLAMMONIUM IONS ON THE SODIUM CURRENT OF THE SQUID GIANT-AXON

The actions of members of the homologous series of alkyl cations CH3(CH2)n-1N+(CH3)3(CnTMA) on the Na current in giant axons of Loligo forbesi were investigated. The substances tested correspond to n = 6, 8, 10, 12, 14 and 16. These cations only produced significant Na current suppression when applied inside the axon. Actions on 1st-pulse Na currents and use-dependent effects were separately studied. The shorter members of the series (C6TMA and C8TMA) produced suppression of 1st-pulse Na currents without causing significant use dependence. The 1st-pulse suppression arose partly from a positive shift along the voltage axis of the steady-state activation parameter (m.infin.) and partly from a reduction in the maximum Na conductance (.hivin.gNa). C12TMA and C14TMA produced little 1st-pulse suppression but caused clear use dependence. C10TMA showed intermediate properties while C16TMA was inactive. The use-dependent actions were quantitatively investigated using a double-pulse protocol. The cations enter a blocking site on the ion-channel via the intra-axonal aqueous phase. The cations appear able to bind to inactivated Na channels at significant rates. The possible molecular locations of the sites responsible for m.infin. shifts and use dependence are discussed. The existence of 2 separate sites may help to explain certain distinctions between the actions of neutral general anesthetics and clinical local anesthetics on the Na channel.