Potassium channels inactivation

Hoshi, T., Zagotta, W. and Aldrich, R. W. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250,533-538,1990. 

Kv 3 -subunits are auxiliary subunits of Shaker-related Kv-channels, which belong to the Kvl subfamily of voltage-gated potassium channels. Kv(3 -subunits may function as chaperones in Kva -subunit assembly and may modulate the gating properties of Kv-channels. In particular, some Kv(3 -subunits may confer a rapid inactivation to otherwise non-inactivating Kv-channels. 

Chen, J., Seebohm, G. and Sanguinetti, M.C. (2002) Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of hERG and eag potassium channels. Proceedings of the National Academy of Sciences of the United States of America, 99, 12461-12466. 

Panyi, G. and Deutsch, C. (2007) Probing the cavity of the slow inactivated conformation of Shaker potassium channels. The Journal of General Physiology, 129, 403-418. 

Outward repolarizing currents oppose the effect of the inward Ica on the plateau phase. This current is carried predominantly through delayed rectifier potassium channels (Ik).These channels are voltage sensitive, with slow inactivation kinetics. Three distinct subpopulations of Ik with differing activation and inactivation kinetics have been described. A rapidly activating subset (Ikf), a slowly inactivating subset (Iks), and an ul-tra-rapidly activating subset to date are identified only in atrial tissue (Ikui)-... 

The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of -90 to -60 mV. During excitation, the sodium channels open, and a fast inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about -95 mV) repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

The potassium channels present in neuronal membranes could also be affected by phenothiazine derivatives. In the study performed by Ogata et al. [255] it was shown that CPZ (9) interfered with several types of potassium channels present in membranes of neurons of the newborn rat cultured dorsal root ganglia. Reversible reduction of the amplitude was found for transient and delayed rectified K+ currents, while inward rectified K+ current remained unaffected by CPZ (9). The block of delayed rectified K+ current by CPZ (9) was, however, less potent than block of the transient one. The hyper-polarizing shift of the steady-state inactivation curve for transient K+ current indicated that CPZ (9) binds preferably to the channels in the inactivated state. 

Final repolarization (phase 3) of the action potential results from completion of sodium and calcium channel inactivation and the growth of potassium permeability, so that the membrane potential once again approaches the potassium equilibrium potential. The major potassium currents involved in phase 3 repolarization include a rapidly activating potassium current (Ikt) and a slowly activating potassium current (Iks)- These processes are diagrammed in Figure 14-3. 

However, it is clear that the calcium/calmodulin pathway can be activated by ACTH [54]. ACTH, like other steroidogenic hormones, increases the influx of calcium into the adrenocortical cell, probably by an action on voltage-sensitive calcium channels [41]. Because stimuli which act only to increase cyclic AMP, such as forskolin, do not enhance calcium influx, it is probable that to some extent the ACTH receptor is coupled to a calcium channel, with intermediacy of a G-protein, or may act by some other mechanism (for example, inactivation of a potassium channel [55]). 

Like the sodium channels, the voltage-gated potassium channels will finally inactivate. This will revert the membrane potential back to normal. 

The potassium channel and the sodium channel undergo inactivation within milliseconds of channel opening (Figure 13.28). A first clue to the mechanism of inactivation came from exposing the cytoplasmic side of either channel to trypsin cleavage by trypsin produced a trimmed channel that stayed persistently open after depolarization. A second clue was the finding that alternatively spliced variants of the potassium channel have markedly different inactivation kinetics these variants differed from one another only near the amino terminus, which is on the cytoplasmic side of the channel. 

Figure 1 (a) The transmembrane topology of a hERG potassium channel subunit is depicted, (b) hERG potassium channel state is dependent on membrane potential. Depolarization favors the open (O) and inactivated (I) states, while hyperpolarization induces channel closing (C). 

Schonherr R, Heinemann SH. 1996. Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. J. Physiol 493(Pt. 3) 63 5 12... 

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