No abstract

No abstract

The permeation properties of ion channels existing in several conductive states were analyzed. Each state was represented by the one-ion model. A special emphasis was placed on features, assumed to be indicative of a multi-ion mode of channel occupancy such as a deviation of concentration dependence of channel conductance from the Michaelis-Menten equation, an anomalous mole fraction effect, a strong voltage dependence of ion block and coupling of unidirectional fluxes (anomalous Ussing flux ratio). The conformational model was shown to have all these properties. The ion permeation through voltage-sensitive calcium channels fulfilled all the characteristics of the model proposed.

1 The whole-cell patch-clamp technique has been used to examine Ca channel currents carried by Ba (IBa) in rat hippocampal neurones.2 Quinacrine selectivity decreased the high-threshold current activated by membrane depolarization from a holding potential of -70 mV. Neither the low-threshold Ca channel current nor the fast tetrodotoxin (TTX)-sensitive sodium current were affected by quinacrine.3 Bath application of quinacrine caused a dose-dependent reduction of the peak amplitude of IBa. This effect was fast, voltage-independent, reversible and had a Kd of 30 ± 5 fAM. 4 The quinacrine-induced block did not change the time-course and the voltage dependence of IBa activation and deactivation. The inhibition revealed no use-dependence, ruling out an open channel block by quinacrine. 5 p-Bromophenacyl bromide had no effect on 'Ba suggesting the lack of involvement of phospholipase A2 in the action of quinacrine. In addition, the quinacrine-induced block was not related to the calmodulin pathway and internal quinacrine did not affect the peak amplitude of IBa.6 The effect of quinacrine on the amplitude of hBa was dependent of the external pH, and suggested that only the single-protonated form of the drug can bind to the channel receptor with a Kd of 3 EM. Quinacrine and other substituted acridines can thus be useful for pharmacological and structure-activity studies of Ca channels.

No abstract