17.5: Ligand- and Voltage- Gated Channels in Neurotransmission

Ligand- and voltage-gated channels play a major role in neurotransmission and muscle contraction by regulating a flow of ions into and out of responding cells. With the advent of the patch-clamp device, it became possible to correlate ion flow with measurements of membrane potential and to define the sequence of electrical and chemical events leading to muscle contraction (Figure 17.10).

Figure 17.10: A patch-clamp device can measure ion flow through voltage-gated channels in a membrane during a depolarization event. After a voltage is applied across the plasma membrane, specific ion sensors measure ion follow into or out of the cell.

17.5.1 Measuring Ion Flow and Membrane Potential with a Patch-Clamp Device

When neurotransmitters bind to their receptors, ion channels in responding neuron or muscle cells open. The resulting influx of \(\rm Na^{+}\) ions disrupts the resting potential of the target cell. The effect is transient if the membrane potential remains negative. But if enough \(\rm Na^{+}\) ions enter the cell, the membrane becomes depolarized. If the cell experiences hyperpolarization, a localized reversal of normal membrane polarity (say from −70 mV to +65 mV or more) will generate an action potential. This action potential will travel like a current along the neural or muscle cell membrane, eventually triggering a physiological response (e.g., the excitation of the next nerve cell in a neuronal pathway or the contraction of the muscle cell).

In this example of patch-clamp measurements, closing the power supply switch sends an electrical charge to the cell, opening a voltage-gated ion channel. A potassium sensor in the device then detects a flow of \(\rm K^{+}\) ions through the channel out of the cell; at the same time, a voltmeter registers the resulting change in membrane potential. In addition to voltage-gated ion channels, the patch-clamp device can measure ion flow through ligand-gated ion channels and mechanically gated ion channels. The former channels are receptor-ion gates that open when they bind an effector molecule.

Mechanically gated ion channels detect physical pressure or stress that cause a local membrane deformation, and then open the channel (recall piezoreceptors discussed earlier).

297 Patch-Clamp Device Records Membrane Potential and Ion Flow

298 Patch-Clamp Measures Resting Potential and Depolarization

299 Gated Ion Channels

300 Two Types of Gated Ion Channels

Finally, cells maintain a high intracellular concentration of \(\rm K^{+}\) ions, causing \(\rm K^{+}\) ions to slowly leak from the cell, a phenomenon detectable by a patch-clamp. \(\rm Cl^{−}\) ions, as well as other, organic, anions inside a cell, limit the leakage, helping to create the relatively electronegative interior of a cell that is its resting potential. The patch-clamp technique has been used to correlate the flow of ions and changes in membrane potential when a neuron fires, causing an action potential in a responding cell (e.g., Figure 17.11).

Figure 17.11: With the patch-clamp device, follow changes in ion flow through gated channels and resulting changes in potential (voltage) across e.g., a muscle cell membrane during an action potential.

In the illustration, follow the opening and closing of ion channels and the resulting flow of ions along their concentration gradients. A shift from resting potential and possibly an action potential will result from facilitated diffusion of specific ions into or out of the cell through gated ion channels that must open and close in sequence. The behavior of two different voltage-gated ion channels is illustrated in the graph. Electrical stimulation opens \(\rm Na^{+}\) channels, allowing \(\rm Na^{+}\) ions to rush into the cell. This reduces the membrane potential from the resting state to zero. If the \(\rm Na^{+}\) influx continues, it can make the cytoplasm more positive than the extracellular fluid, which may lead to an action potential. If the reversal in polarity is high enough, a voltage-gated K+ opens, and potassium ions rush out of the cell, restoring the resting potential of the cell.

A cell can continue to respond to stimuli with action potentials for as long as there is sufficient \(\rm Na^{+}\) outside the cell and \(\rm K^{+}\) inside the cell. While active transport of \(\rm Na^{+}\) and \(\rm K^{+}\) is not required to reestablish the resting potential, it will eventually be necessary to restore the balance of the two cations in the cell. If a nerve or muscle cell fires several times (or even if it just leaks ions), the [\(\rm K^{+}\)] inside the cell and the [\(\rm Na^{+}\)] outside the cell can drop to a point where the cell can’t generate an action potential when stimulated. The role of ATP-dependent \(\rm Na^{+}\)/\(\rm K^{+}\) pump is, ultimately, to restore the \(\rm Na^{+}\)/\(\rm K^{+}\) balance across the responding cell membrane. As we have seen, each cycle of pumping exchanges three \(\rm Na^{+}\) ions from the intracellular space for two \(\rm K^{+}\) ions from the extracellular space. Operation of this ion pump has two effects:

• It restores \(\rm Na^{+}\) concentrations in the extracellular space relative to the cytoplasm.
• It restores \(\rm K^{+}\) concentrations in the cytoplasm relative to the extracellular space.

301 Gated Ion Channels Open & Close in Order during an Actual Potential

Together with the higher negative-ion concentrations in the cytosol, the unequal exchange of \(\rm Na^{+}\) for \(\rm K^{+}\) ions maintains the resting potential of the cell over the long term and ensures that nerve and muscle cells remain excitable. Next, we will take a closer look at the role of both ligand-gated and voltage-gated ion channels in neurotransmission.

17.5.2 Ion Channels in Neurotransmission

Action potentials result in an orderly, sequential opening and closing of voltage- and ligand gated channels along the neuronal axon. In the following link, you can see the sequential cycles of voltage-gated channels that propagate a localized action potential (membrane depolarization) along an axon toward a synapse.

302 Propagating an Action Potential along an Axon

When a propagated depolarization reaches a synapse, gated ion channels either open or close in the neuron and the responding cell. The cooperation of voltage- and ligand-gated channels at a neuromuscular junction is illustrated in Figure 17.12 (below).

Figure 17.12: Neurotransmission starts with an action potential in the cell body of a neuron. The action potential is propagated along the axon to the nerve terminal synapse. The depolarization pulse initiates \(\rm Ca^{++}\) flow into the neuron through voltage-gated channels. This causes a release of neurotransmitters into the synaptic cleft. The neurotransmitter binds to a ligand-gated channel on the responding cell, causing Na+ ions to flow into the responding cell and leading to an action potential.

As you can see from the illustration, after a neuron fires, a moving region of hyperpolarization (an electrical impulse) travels down the axon to the nerve ending. At the nerve ending, the traveling charge difference (electrical potential) across the cell membrane stimulates a \(\rm Ca^{++}\)-specific voltage-gated channel to open. \(\rm Ca^{++}\) ions then flow into the cell because they are at higher concentrations in the synaptic cleft than in the cytoplasm. The \(\rm Ca^{++}\) ions cause synaptic vesicles to fuse with the membrane at the nerve ending, thereby releasing neurotransmitters into the synaptic cleft; these cross the cleft and bind to a receptor on the responding cell’s plasma membrane. This receptor is a ligand-gated channel (also called a chemically gated channel). Binding of the neurotransmitter ligand opens the gated channel. The rapid diffusion of \(\rm Na^{+}\) ions into the cell then creates an action potential that leads to the cellular response—in this case, muscle contraction. We have already seen the role of \(\rm K^{+}\) channels in restoring the membrane resting potential after an action potential, and we have seen the role of the sodium/potassium pump in restoring the cellular \(\rm Na^{+}\)/\(\rm K^{+}\) balance.

303-2 The Role of Gated Ion Channels at a Neuromuscular Junction

CHALLENGE

Many of the neurotoxic snake and spider venoms interfere with ion channels to paralyze and immobilize prey organisms. Which of the channels mentioned here would you expect to be affected by these neurotoxins (or for that matter, neurotoxic gases), and why?