Ion Channel Gating

Ion channels undergo a conversion between two types of states—closed and open—in a process referred to as gating. The gating behavior of an ion channel defines its functional role in physiology and is typically tied to the name of the ion channel. Ion channels are able to respond to a wide range of stimuli. The binding of a neurotransmitter (ligand-gated ion channels), a change in the membrane potential (voltage-gated ion channels), a physical pull on the ion channel protein (mechanosensitive ion channels), and heat are known to activate certain ion channels.

An ion channel with two states, one closed and one open, can be represented by a state diagram:

where C stands for closed and O stands for open. The C— O transition is referred to as activation; the reverse process, O — C, is called deactivation. Since ion channels are metastable and can exist in multiple states, there is no way of knowing a priori which state a single ion channel will be in at any moment in time. After observing the activity of an ion channel for some length of time, however, one can collect statistics that describe the probability that an ion channel will be in the closed or open state, the average duration of each closing and opening, and the frequency of switching between states. These parameters are part of a set of fundamental variables that uniquely describe the activity of an ion channel. A stimulus can activate the ion channel by destabilizing the closed state or stabilizing the open state and thus increase the probability that an ion channel will be in the open state. A closed state that is accessed after the ion channel opens is referred to as the inactive state (I). An ion channel with three states may have the following state diagram:

The O —I transition is referred to as inactivation. Often, the state diagrams of ion channels are complex and can contain multiple interconnecting closed, open, and inactive states.

The physical change in the ion channel structure that is responsible for gating remains an area of active research. Studies of several model ion channels have revealed a range of mechanisms by which ion channels may gate. For one channel, the nicotinic acetylcholine receptor (nAChR), scientists have been able to get a glimpse of the gating process with the use of the electron microscopy. Thus far, this has only been possible for the nAChR because the Torpedo electric ray produces abundant amounts of this protein that can form crystalline arrays in the membrane. These images revealed that this ion channel has an outer vestibule that makes it a great deal longer than the vertical height of the plasma membrane. Images taken before and after treatment with acetylcholine have been used to model the conformational changes that occurred after ligand binding. The binding site for acetylcholine lies on the outer vestibule, and the binding of ligand is transduced as a signal to the transmembrane segments that then undergo a concerted change in structure to open the pore. Unfortunately, the resolution of these images is too low to provide a detailed view of the gating process. One model postulates that the pore is lined by ''kinked helices'' whose vertices project into the pore in the closed state. After treatment with acetylcholine, the kinked helices appear to rotate away from the pore. This rotation may move hydrophobic residues that block the pore out of the way and replace them with polar residues.

Another well-studied gating mechanism is the inactivation gating of voltage-gated potassium channels (Fig. 6b). Inactivation can be eliminated, while other properties are left intact, by treating the inside of the channel with proteases. This and other experimental observations of the inactivation process can be explained by a ''ball-and-chain'' mechanism. In this model, part of the ion channel that binds the pore (ball) is tethered to the ion channel by a linker (chain) and blocks the pore once the channel has been activated. The region of the ion channel that forms the ball can be expressed by itself. As further evidence of this mechanism, when the ball is directly applied onto protease-treated ion channels, inactivation can be restored.

Inward rectifier potassium channels illustrate that the gate does not need to be an intrinsic part of the ion channel (Fig. 6c). Inward rectifying potassium channels pass larger currents into the cell than out of the cell. The channel alone, however, exhibits little or no rectification but displays rectification when it is brought near a cell, suggesting that a soluble factor is involved. In the case of inward rectifier potassium channels, it was discovered that Mg2+ and

Ion Channel Cartoon

Figure 6 Three examples of ion channel gating mechanisms depicted as a cartoon. (a) Gating occurs via a generalized change in the structure in the region of the pore. The nicotinic acetylcholine receptor undergoes a conformational change of its M2 segment that closes the ion conduction pathway. (b) "Ball-and-chain" mechanism of inactivation gating in voltage-gated potassium channels. (c) Inward rectifiers are gated by extrinsic factors (e.g., Mg2+) that block the pore. The block is voltage dependent; therefore, inward rectifiers conduct more current below Ek and little current above EK.

Figure 6 Three examples of ion channel gating mechanisms depicted as a cartoon. (a) Gating occurs via a generalized change in the structure in the region of the pore. The nicotinic acetylcholine receptor undergoes a conformational change of its M2 segment that closes the ion conduction pathway. (b) "Ball-and-chain" mechanism of inactivation gating in voltage-gated potassium channels. (c) Inward rectifiers are gated by extrinsic factors (e.g., Mg2+) that block the pore. The block is voltage dependent; therefore, inward rectifiers conduct more current below Ek and little current above EK.

polyamines, amino acid metabolites, produced rectification by binding to the pore of the channel at depolarized membrane potentials but not at hyperpo-larized membrane potentials.

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