Channel gating

In the actual situation, there are many channels that may be represented by a surface layer of distributed dipoles. This layer can at a distance be simplifled to one net dipole representing one or more cells. 

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Electrophysiological studies (mainly using voltage-clamp and patch clamp) revealed the essential properties of the sodium channels kinetics of channel gating and selective ion permeation. Sodium channels are... 

Figure 2. Kinetic schemes for Na channel gating (right) and the graphed time-course for single channels (solid lines, the higher position is open ) and for the population of many channels (broken line, the fraction open increases upwardly). Numbers at the arrows of the kinetic scheme are the rate constants, in 10 sec" The period of simulation is 5 msec. Computerized model courtesy of Dr. Daniel Chemoff.

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. 

At first these effects of activators may appear complicated, requiring multiple factors to explain the total response, but reference to the kinetic model for channel gating (Figure 2) clarifies the complexity. Activators may produce spontaneous opening... 

By interfering with any one of the many phases associated with these second messenger pathways, toxins may alter channel gating. For example, the blue green algal toxins, aplysiatoxin, and lyngbyatoxin bind to and activate protein kinase C in a manner similar to phorbol esters (73). They also stimulate arachidonic acid metabolism (74). The coral toxin, palytoxin, also stimulates arachidonic acid breakdown albeit by an unknown mechanism (74) and affects other biochemical activities of the cell (see chapters by Fujiki et al., Wattenberg et al., and Levine et al., this volume). 

Exactly how this transporter carries noradrenaline across the neuronal membrane is not known but one popular model proposes that it can exist in two interchangeable states. Binding of Na+ and noradrenaline to a domain on its extracellular surface could trigger a conformation change that results in the sequential opening of outer and inner channel gates on the transporter. This process enables the translocation of noradrenaline from the extracellular space towards the neuronal cytosol. 

Bormann, J, Hamill, OP and Sakmann, B (1987) Mechanism of anion permeation through channels gated by glycine and y-aminobutyric acid in mouse cultured spinal neurones. J. Physiol. (Lond). 385 243-286. 

French, R. J., and R. Horn, Sodium channel gating models, mimics and modifiers, Ann. Rev. Biophys. Bioeng., 12, 319 (1983). 

Changes in the occupancy of the open-channel state of the receptor as a function of time (pA2R (t)) in response to a perturbation of the receptor equilibrium can be used to obtain information about the rates of channel gating and the interaction of dmgs with ion-channel receptors. The system is said to relax towards a new equilibrium. The time course of the relaxation is used to measure rates from the average behavior of many ion channels in a recording, while noise analysis uses the frequency of the moment-to-moment fluctuations in occupancy of the open-channel state at equilibrium to provide information about the rates in the receptor mechanism. 

P Hess, JB Lansman, RW Tsien. (1984). Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311 538-544. 

Induction of repetitive activity in the nervous system is the principal effect of pyrethroids. Repetitive activity originates from a prolongation of the transient increase in sodium permeability of the nerve membrane associated with excitation. All pyrethroids affect sodium channel gating in a similar manner, although Type II pyrethroids are significantly more neurotoxic than Type I pyrethroids. 

Sitsapesan R, Williams AJ 2000 Do inactivation mechanisms rather than adaptation hold the key to understanding ryanodine receptor channel gating J Gen Physiol 116 867-872 Somlyo AP 1985 Excitation-contraction coupling and the ultrastructure of smooth muscle. Circ Res 57 497-507... 

Cox DH, Aid rich RW 2000 Role of the /) 1 subunit in large-conductance Ca2+-activated K+ channel gating energetics mechanisms of enhanced Ca2+ sensitivity. J Gen Physiol 116 411-432... 

Tieleman, D. P., Shrivastava, I. H., Ulmschneider, M. R., and Sansom, M. S. (2001) Pro-line-induced hinges in transmembrane helices possible roles in ion channel gating. Proteins 44, 63-72. 

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