Inactivation closed-state

Figure 2 Hinged-lid model of fast inactivation of Na+ channels. Bird s eye view of the channel that consists of four similar repeats (l-IV). The channel is shown cut and spread open between repeats I and IV to allow a view of the intracellular loop between repeats III and IV. The loop acts as the inactivation gate whose hinge GG (a pair of glycines) allows it to swing between two positions the open channel state and the inactivated closed state where the inactivation particle IFM (the amino acids isoleucine, phenylalanine, and methionine) binds to its acceptor.

The localization of adducts to the epicardial border zone suggested the possibility that IsoK/LG adducts contribute to cardiac arrhythmias. Ventricular tachycardia/fibrillation following myocardial infarction is a major cause of sudden cardiac death. Arrhythmias in ischemic myocardium arise from sodium channel blockade. Sodium channels are hypothesized to cycle between three conformational states a deactivated closed state, an activated open state, and an inactivated closed state. Upon depolarization, the deactivated state converts to the activated state and sodium current flows for a brief time before the channel enters the inactive state. The channel only converts from the inactive state to the deactivated state when the membrane repolarizes during the falling phase of the action potential. Changes in the ability to convert from the inactive to the deactivated state are critical to the initiation and perpetuation of arrhythmias. 

Like other voltage-gated cation channels, Ca2+ channels exist in at least three states A resting state stabilized at negative potentials (such as the resting potentials of most electrically excitable cells) that is a closed state from which the channel can open. The open state is induced by depolarization. Channels do not stay open indefinitely because they are turned off during prolonged depolarization by transition into an inactivated state. Inactivation is driven both by depolarization... 

Activation is slower in less depolarized membranes and inactivation drains the open (and resting) state more effectively. In fact, real Na" " channels gate by more complex pathways, including several closed states intermediate between R and O, as well as multiple inactivated states. Inactivation from these intermediate states is probably faster than from / , and the entire activation process, in its fully branched entirety, is rich with kinetic possibilities. However, the effects of toxins may be understood in general by the simpler scheme presented in Figure 2. 

Cummins, T. R., Howe, J. R., Waxman, S. G. Slow closed-state inactivation a novel mechanism... 

Cummins, T. R., Aglieco, F., Renganathan, M., Herzog, R. I., Dib-Hajj, S. D., Waxman, S. G. Nav1.3 sodium channels Rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons, J. Neurosci. 2001, 21, 5952-5961. 

G784S- CAE decreased rate of activation and increased rate of closed state inactivation (Vitko et al., 2005) no change in channel properties (Peloquin et al., 2006)... 

Patil PG, Brody DL, Yue DT (1998) Preferential closed-state inactivation of neuronal calcium channels. Neuron 20 1027-1038. 

The effect of diethylamine (DEA) on the conductance of a single Na channel is depicted in Figure 5.5a. In the control trace, the channel can be seen to oscillate between two states of conductance, with currents of 0 and 1 pA, respectively. A conductance of 0 would be expected for the closed and the inactivated states, respectively, whereas the conductance of 1 pA would represent the open state. This illustrates a very neat feature of the single channel recording techniques - they let us observe the discrete and stochastic nature of conformational changes of the proteins in a much more direct fashion than typically possible with other allosteric proteins (e.g., enzymes or hormone receptors). In the presence of DEA, open and closed state still alternate, but the conductance of the open state is reduced by about 40%, indicating a partial blockade of the channel. 

At the resting potential, the open probability of voltage-gated cation channels is extremely low, which indicates that very few channels open randomly. Depolarization causes channel activation by markedly increasing open probability. During maintained depolarization, open probability is reduced time-dependently and not voltage-dependently by channel inactivation, which leads to a closed state from which the channels cannot be reactivated immediately. Instead, inactivated channels require repolarization and a certain time for recovery from inactivation. On the other hand, repolarization of the membrane prior to the process of inactivation will deactivate the channel (i.e., reverse activation that leads to the closed resting state from... 

Figure 13.29. Ball-and-Chain Model for Channel Inactivation. The inactivation domain, or "ball" (red), is tethered to the channel by a flexible "chain" (green). In the closed state, the ball is located in the cytosol. Depolarization opens the channel and creates a negatively charged binding site for the positively charged ball near the mouth of the pore. Movement of the ball into this site inactivates the charmel by occluding it. [After C. M. Armstrong and F. Bezanilla. J. Gen. Physiol. 70(1977) 567.]...

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). 

Waxman Ted Cummins, you have thought a lot about the slowness of closed-state inactivation in the hNE channel, and Bruce Bean, you have thought about the resurgent current produced putatively by Na 1.6. Are there any clues in either of those sets of observations ... 

Cummins The striking feature to me of that closed state inactivation is the difference between, say, the PNl neuronal channel and the skeletal muscle. It is a major difference, but 1 don t know what the underlying mechanism is. 

Strichart It is something that is seen in frog node. With normal Na gradients this is something that is seen as channels are driven through the reversal potential to yield outward current. I wondered whether this might not be due to the possibihty that the last closed state — or the pre-open state, if you will— can go to an inactivated state, a pathway which may be relatively favoured for the smaller depolarizations, but larger depolarizations may inactivate channels faster from the open state, an inactivation state that may be more reversible. 

Cummins At least from my evidence concerning closed state inactivation of Na channels (Cummins et al 1998), it might be that the inactivation is dependent on the channels opening for the peripheral neuronal channels, as opposed to skeletal muscle channels, which are more likely to inactivate from the closed states. This may be why you see such a concordance between the Hinf (steady-state inactivation curve) and the voltage-dependence of the persistent current the peripheral neuronal Na channels may have to open if they are going to inactivate. 

Cummins TR, Howe JR, Waxman SG 1998 Slow closed-state inactivation a novel mechanism underlying ramp currents in cells expressing hNE/PNl sodium channels. J Neurosci 18 9607-9619... 

Striciiart When you did the cross linking in the condition where the inactivation gate was in the closed state, and you showed that there was a reduction in peak current, it seemed to me that the sustained current for that particular trace was unaffected by that procedure. Did you notice that ... 

Bean What is your mental picture for what is happening when the photoreaction occurs with the inactivation gate in the closed state How does the label change inactivation ... 

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