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