In light of the recent identification of a class of voltage-dependent Na+ channels with a comparatively weak peak conductance/voltage relationship, this article reviews the structural elements by which proteins are rendered voltage-dependent and the manner in which these proteins are studied. The physicochemical principles used to analyze voltage-dependent ionic channels are reviewed, together with examples drawn from Na+ currents recorded from the somatic membranes of dorsal root ganglion neurons. The structure of the voltage dependent Na + channel and known structural/functional correlates are described. A functional definition of ionic channels with weak voltage-dependence and a discussion of inherent pitfalls of classical analytic methods when applied to the study of such channels are offered. Ultimately, determining how these channels function as they do, i.e., elucidating their gating properties, will be accomplished by cloning and reexpressing the channels in otherwise non-excitable cell systems, and recording their gating currents. Na+ and K+ channels with weak voltage-dependence may serve an important functional role by modulating threshold in excitable cells. NEUROSCIENTIST 3:102-111, 1997
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