Biophysics of a Trespasser Na 1 Block of Ca 2 1 Channels

Why were Hodgkin and Huxley so disappointed with their work? Through a brilliant train of thought that considered the linearity of the current-voltage curve and the relative amplitudes of ionic and gating currents (Hodgkin and Huxley, 1952), they concluded that the Na 1 current which drives the action potential passes through a channel—defined as a pore that passes ions at high rates compared to enzyme or carrier turnover. It is often forgotten that this disproved their working hypothesis. Reasoning that the high selectivity of the molecule responsible for Na 1 permeation was inconsistent with high flux, they had predicted a Na 1 selective carrier, not a pore (Hodgkin et al., 1949; also, see Fig. 7 in Hodgkin, 1976, from an unpublished manuscript). We now take for granted that pores can bind their preferred ion and still pass millions per second, but, although it may be taken for granted, it is not understood. Bezanilla and Armstrong (1972) succinctly showed that a single binding site in a rigid pore cannot generate selective flux. The problem is clear: if a selectivity site binds ion A far more tightly than ion B, then A exits the pore far slower than B, and A’s advantage in pore occupancy is negated. Always precise, Hodgkin and Huxley never once used the word “channel” in their set of papers that serve as the discovery site for Na 1 and K 1 channels. Concluding that they could not provide a plausible molecular mechanism for the Na 1