Single cardiac transmembranous Ca channels have three modes of gating behaviour in the absence of drugs, expressed as current records with brief openings (mode 1), with no openings because of channel unavailability (mode 0 or null mode) and with long-lasting openings and very brief closings that appear only rarely (mode 2). The dihydropyridine Ca agonist Bay K 8644 enhances Ca channel current by promoting mode 2, while the Ca antagonists nitrendipine and nimodipine inhibit the current by favouring mode 0.

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Calcium channels carry out vital functions in a wide variety of excitable cells but they also face special challenges. In the medium outside the channel, Ca2+ ions are vastly outnumbered by other ions. Thus, the calcium channel must be extremely selective if it is to allow Ca2+ influx rather than a general cation influx. In fact, calcium channels show a much greater selectivity for Ca2+ than sodium channels do for Na+ despite the high flux that open Ca channels can support. Relatively little is known about the mechanism of ion permeation through Ca channels. Earlier models assumed ion independence or single-ion occupancy. Here we present evidence for a novel hypothesis of ion movement through Ca channels, based on measurements of Ca channel activity at the level of single cells or single channels. Our results indicate that under physiological conditions, the channel is occupied almost continually by one or more Ca2+ ions which, by electrostatic repulsion, guard the channel against permeation by other ions. On the other hand, repulsion between Ca2+ ions allows high throughput rates and tends to prevent saturation with calcium.

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Single channel and whole cell recordings were used to study ion permeation through Ca channels in isolated ventricular heart cells of guinea pigs . We evaluated the permeability to various divalent and monovalent cations in two ways, by measuring either unitary current amplitude or reversal potential (E,e,,). According to whole cell measurements of E,,,,, the relative permeability sequence is Ca" > Sr" > Ba 2+ for divalent ions ; Mg`is not measurably permeant . Monovalent ions follow the sequence Li' > Na' > K' > Cs', and are much less permeant than the divalents . These whole cell measurements were supported by single channel recordings, which showed clear outward Thus, ions with a higher permeability, judged by Ere, have lower ion transfer rates . In another comparison, whole cell Na currents through Ca channels are halved by <2 uM [Ca] o , but >10 mM [Ca]. is required to produce half-maximal unitary Ca current . All of these observations seem consistent with a recent hypothesis for the mechanism of Ca channel permeation, which proposes that : (a) ions pass through the pore in single file, interacting with multiple binding sites along the way ; (b) selectivity is largely determined by ion affinity to the binding sites rather than by exclusion by a selectivity filter ; (c) occupancy by only one Ca ion is sufficient to block the pore's high conductance for monovalent ions like Na' ; (d) rapid permeation by Ca ions depends upon double occupancy, which only becomes significant at millimolar [Ca], because of electrostatic repulsion or some other interaction between ions ; and (e) once double occupancy Address reprint requests to Dr.