Abstract
An ever-growing body of evidence has shown that voltage-gated ion channels are likely molecular systems that display hysteresis in their activity. This phenomenon manifests in the form of dynamic changes in both their voltage dependence of activity and their deactivation kinetics. The goal of this review is to provide a clear definition of hysteresis in terms of the behavior of voltage-gated channels. This review will discuss the basic behavior of voltage-gated channel activity and how they make these proteins into systems displaying hysteresis. It will also provide a perspective on putative mechanisms underlying hysteresis and explain its potential physiological relevance. It is uncertain whether all channels display hysteresis in their behavior. However, the suggested notion that ion channels are hysteretic systems directly collides with the well-accepted notion that ion channel activity is stochastic. This is because hysteretic systems are regarded to have “memory” of previous events while stochastic processes are regarded as “memoryless.” This review will address this apparent contradiction, providing arguments for the existence of processes that can be simultaneously hysteretic and stochastic.
Highlights
When thinking about a physical or chemical system that responds to a “stimulus,” it is commonly assumed that such system would display a constant activity-vs.-stimulus relationship
The receptor does not “remember” what happened before the ligand was at the current concentration, what the concentration of the ligand had been in the past, or what levels of activation were previously reached
The fraction of the total charge in each mode is a function of the holding membrane potential. This indicates that modes of activity in a voltagesensing domain (VSD) are likely discrete sets of states, that channel activity can have more than one of these modes of activity, and that channels can adopt any of these modes one at a time
Summary
When thinking about a physical or chemical system that responds to a “stimulus,” it is commonly assumed that such system would display a constant activity-vs.-stimulus relationship. The level of activity of the receptor will only depend on the current concentration of the agonist ligand This will always be the case regardless of how the ligand concentration changes. Let us consider a tetrameric voltage-gated cation-selective channel that has three effective sensing charges per subunit and that reaches half of its maximum activity at 0 mV Assuming that it does not inactivate, this channel will be at 0.1% of its maximum activity when the membrane potential is −60 mV, while reaching about 99% of its maximum at a membrane. A growing body of evidence shows that the electrical sensitivity of voltage-gated channels can be dynamic rather than static This dynamic character of the voltage dependence seems to be rooted in the hysteretic behavior of channels and has important consequences on the physiology and pharmacology of these proteins. Hysteresis seems to play a critical role in the generation and modulation of electrical signal events in neurons, muscles, and other excitable tissues
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