Whether "Slip-Mode Conductance" Occurs

Excitable cells rely on selective ionic conductances for electrical signaling. The work of Hodgkin and Huxley (1) propelled the modern dissection of the mechanisms of selectivity. Their formulation postulated two independent sets of ionic conductances, Na+ and K+, whose relative permeabilities changed during the course of excitation. Mullins subsequently proposed that Na+ and K+ traverse the membrane through a single set of pores that changed from being Na+-selective to K+-selective (2). That view is no longer held as tenable. Several lines of experimental evidence, notably single-channel recordings, established convincingly that the membrane contains distinct sets of pores, each with its own distinctive selectivity properties (3, 4). Nevertheless, the prevailing view that ion channel selectivity is preserved during normal electrical activity was recently challenged in a report by L. F. Santana et al. (5). Voltage clamp experiments in rat ventricular cells led to the proposal that voltage-dependent Na+ channels change their selectivity in response to cyclic AMP–dependent phosphorylation. Unexpectedly, such channels conduct Ca2+ well; similar "slip-mode conductance" responses were seen during exposure to cardiac glycosides. The extensive evidence against flexible selectivity, as well as major technical concerns over that report (5), prompted us to question whether or not this idea has a genuine biological basis. Ventricular myocytes are large cells in which voltage control is notoriously difficult to achieve (6); the large number of Ca2+-sensitive ionic currents (7) further complicates the interpretation of the results. To test for the existence of slip-mode conductance, we expressed human hH1 (8) or rat rH1 (9) cardiac Na+ channels heterologously in Chinese hamster ovary (CHO) cells. These small cells are readily voltage-clamped, have few endogenous channels, and support cyclic AMP-mediated responses (10).