Light at the End of the Channel

Previews the optical signals associated with each probe as the Light at the End of the Channel channels gate. These site-specific fluorescence signals report the goings-on in individual domains, in contrast to conventional electrical signals, to which all four subunits The propagation of action potential spikes along neu-necessarily contribute. The results show that the four ronal membranes is a feature of the nervous system so domains of Na ϩ channels are functionally nonequivalent: fundamental and so well known as to seem common-they have distinct gating personalities. place. But the molecular foundation of this familiar bio-The specific focus of this study is a classical topic in logical phenomenon—the voltage-dependent confor-Na ϩ channels: the coupling of voltage-dependent acti-mational changes leading to opening of Na ϩ , K ϩ , and vation to channel inactivation, a separate gating process Ca 2ϩ channels—presents puzzles in protein behavior that ensures swift, reliable spike repolarization. Many unencountered elsewhere in macromolecular chemistry. S4-type channels spontaneously inactivate upon sus-How is the membrane electric field sensed by these tained depolarization, and it is now widely accepted that proteins? By what sort of allosteric gymnastics do the inactivation is directly coupled to channel opening. In proteins respond to changes in transmembrane voltage its simplest form, this idea demands that only the open as they switch among closed and open conformations? conformation of the channel is capable of inactivating. These kinds of questions have provided most of the Conversely, inactivated channels cannot directly close driving force for research in ion channel biophysics since upon repolarization, but must first emerge out of the Hodgkin and Huxley (1952) created the field a half-cen-inactivated state into the open state. This effect was first tury ago. It is only in the past few years, however, that we observed in groundbreaking measurements of charge have begun to derive convincing pictures of the physical movement (" gating currents ") by Armstrong and Bezan-movements that occur upon voltage gating of channels. illa (1977) in Na ϩ channels. Depolarization elicits prompt These recent advances have all emerged from juxtapos-on gating currents, as the S4 segments, poised for the ing the usual electrophysiological measurements with activating voltage change, move outward as the first clever chemical interventions. Thus, Horn's group (Yang step toward channel opening. However, once the chan-and Horn, 1995) introduced a molecular cherry-picking nel has opened and then inactivated a few milliseconds method to show that the charge-laden " …