No abstract

After channel activation, and in some cases with sub-threshold depolarizing stimuli, Kv channels undergo a time-dependent loss of conductivity by a family of mechanisms termed inactivation. To date, all identified inactivation mechanisms underlying loss of conduction in Kv channels appear to be distinct from deactivation, i.e. closure of the voltage-operated activation gate by changes in transmembrane voltage. Instead, Kv channel inactivation entails entry of channels into a stable, non-conducting state, and thereby functionally reduces the availability of channels for opening. That is, if a channel has inactivated, some time must expire after repolarization of the membrane voltage to allow the channel to recover and become available to open again. Dramatic differences between Kv channel types in the time course of inactivation and recovery underlie various roles in regulating cellular excitability and repolarization of action potentials. Therefore, the range of inactivation mechanisms exhibited by different Kv channels provides important physiological means by which the duration of action potentials in many excitable tissues can be regulated at different frequencies and potentials. In this review, we provide a detailed discussion of recent work characterizing structural and functional aspects of Kv channel gating, and attempt to reconcile these recent results with classical experimental work carried out throughout the 1990s that identified and characterized the basic mechanisms and properties of Kv channel inactivation. We identify and discuss numerous gaps in our understanding of inactivation, and review them in the light of new structural insights into channel gating.

In human myocardium, the nature of the K+ currents mediating repolarization of the action potential is still speculative. Delayed rectifier channels have recently been cloned from human myocardium, but it is unclear whether or not these currents are involved in the termination of the cardiac action potential plateau. In intact human atrial myocytes, we have identified a rapid delayed rectifier K+ current with properties and kinetics identical to those expressed by a K+ channel clone (fHK) isolated from human heart and stably incorporated into a human cell line for the first time. The myocyte current amplitude was 3.6 +/- 0.2 pA/pF (at +20 mV, n = 15) and activated with a time constant of 13.1 +/- 2 milliseconds at 0 mV (n = 15). The half-activation potential (V0.5) was -6 +/- 2.5 mV (n = 10) with a slope factor (k) of 8.6 +/- 2.2 (n = 10). The heterologously expressed fHK current amplitude was 136 pA/pF (at +20 mV, n = 9) with an activation time constant of 11.8 +/- 4.6 milliseconds at 0 mV; V0.5 was 4.1 +/- 2.4 mV (mean +/- SEM, n = 8); and k was 7.0. The conductance of single fHK channels was 16.9 picosiemens in 5 mM bath K+. Both native and cloned channel currents inactivated partially during sustained depolarizing pulses. Both currents were blocked by micromolar concentrations of 4-aminopyridine and were relatively insensitive to tetraethylammonium ions and class III antiarrhythmic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

These data suggest that RSD1235's clinical selectivity and AF conversion efficacy result from block of potassium channels combined with frequency- and voltage-dependent block of INa.

In voltage-activated ion channels, voltage sensor (VSD) activation induces pore opening via VSD-pore coupling. Previous studies show that the pore in KCNQ1 channels opens when the VSD activates to both intermediate and fully activated states, resulting in the intermediate open (IO) and activated open (AO) states, respectively. It is also well known that accompanying KCNQ1 channel opening, the ionic current is suppressed by a rapid process called inactivation. Here we show that inactivation of KCNQ1 channels derives from the different mechanisms of the VSD-pore coupling that lead to the IO and AO states, respectively. When the VSD activates from the intermediate state to the activated state, the VSD-pore coupling has less efficacy in opening the pore, producing inactivation. These results indicate that different mechanisms, other than the canonical VSD-pore coupling, are at work in voltage-dependent ion channel activation.