Ion channel diversity

Various types of ion channels help regulate cellular processes

Ion channels are found in all cells. The properties of voltage-gated Na ⁺ and K ⁺ channels, which are essential for generating the AP in nerve axons and skeletal muscle cells, are described in Chapter 7 . Many other types of ion channels also play important roles in regulating membrane electrical activity. Table 8.1 lists some examples. Each of the ion channel types is defined by a combination of specific physiological, pharmacological, and structural characteristics. As an example, the characteristics of voltage-gated Na ⁺ channels in nerve axons include, in part, Na ⁺ selectivity, voltage-dependent activation, fast inactivation, and high-affinity block by tetrodotoxin. In this chapter we focus on the properties of several other physiologically important channels. These examples illustrate the diversity of ion channel types, the variety of roles they play in normal cell function, and their pathophysiology. Ion channels that open after the binding of a neurotransmitter or other chemical activator, called ligand-gated ion channels, are discussed in Chapters 12 and 13 .

Voltage-gated Ca ²⁺ channels contribute to electrical activity and mediate Ca ²⁺ entry into cells

Ion channels that selectively allow Ca ²⁺ ions to permeate are of vital importance in the normal functioning of nearly all cells. All excitable cells have Ca ²⁺ channels. In some cells, voltage-gated Ca ²⁺ channels can generate APs in the absence of Na ⁺ channels. However, in many cells that express both voltage-gated Na ⁺ and Ca ²⁺ channels, Ca ²⁺ channel activity modifies the shape of the AP. Ca ²⁺ channels contribute to the APs generated in the heart ( Fig. 8.1 ), some endocrine cells (e.g., pancreatic β-cells), and specific regions of neurons (e.g., dendrites and nerve terminals).

Ca ²⁺ channels influence a wide range of cellular activities by allowing Ca ²⁺ ions to enter the cell. The extracellular free Ca ²⁺ concentration is approximately 1 mM (10 ⁻³ M), whereas [Ca ²⁺ ] _i is normally approximately 0.0001 mM (10 ⁻⁷ M). This means that E _Ca is approximately +120 mV. Therefore, when a Ca ²⁺ channel opens, Ca ²⁺ ions flow into the cell down their electrochemical gradient. Because [Ca ²⁺ ] _i is normally very low, a relatively small influx of Ca ²⁺ can produce a significant increase in [Ca ²⁺ ] _i . [Ca ²⁺ ] _i directly regulates secretion, contraction, energy metabolism, ion channel activity, and numerous other processes.

Several distinct types of voltage-gated Ca ²⁺ channels have been identified based on their physiological, pharmacological, and structural properties ( Box 8.1 and Table 8.2 ). Indeed, several Ca ²⁺ channel mutations have been identified that are associated with hereditary diseases. One example is X-linked congenital stationary night blindness. This is caused by loss-of-function mutations in the L-type Ca ²⁺ channel subtype that is expressed in photoreceptors ( Box 8.2 ).

Ca ²⁺ currents can be recorded with a voltage clamp

Voltage-gated Ca ²⁺ channels can be studied with the voltage clamp. Whole-cell currents recorded from a neuronal cell body with a voltage clamp are shown in Fig. 8.2 . With K ⁺ channels blocked, a depolarizing voltage clamp step evokes an inward current that has both a fast transient component and a more sustained component. The fast transient component of the current is generated by Na ⁺ channels. When external Na ⁺ is removed, the Na ⁺ channels no longer conduct inward current (because there are no Na ⁺ ions to flow into the cell), and the remaining inward current is carried by Ca ²⁺ ions flowing into the cell through voltage-gated Ca ²⁺ channels ( Fig. 8.2 ). The Ca ²⁺ channels activate more slowly than Na ⁺ channels. Furthermore, the magnitude of the Ca ²⁺ current ( I _Ca ) decreases very slowly over tens of milliseconds. This indicates that Ca ²⁺ channels inactivate slowly (much more slowly than Na ⁺ channels). Inactivation also is incomplete, so that Ca ²⁺ current can continue to flow during maintained depolarization. The maximum amplitude of the Ca ²⁺ current (∼100 μA/cm ² of membrane area) is usually smaller than the Na ⁺ or K ⁺ currents in axons.

The relationship between Ca ²⁺ channel open probability and V _m is similar to that for voltage-gated Na ⁺ channels, except that the channels activate over a more depolarized voltage range. In some cell types, voltage-gated Ca ²⁺ channels can generate calcium action potentials (Ca ²⁺ APs) in a manner similar to Na ⁺ channels. A depolarizing stimulus opens Ca ²⁺ channels, and Ca ²⁺ ions flow into the cell down their electrochemical gradient. This Ca ²⁺ current further depolarizes the cell and opens more channels. The positive feedback of membrane depolarization on channel opening produces the Ca ²⁺ AP upstroke. Compared with axonal APs generated by Na ⁺ channels, pure Ca ²⁺ APs have slower upstrokes and longer durations because the Ca ²⁺ channels activate more slowly than Na ⁺ channels, and inactivation is slow and incomplete. Ca ²⁺ APs also have lower amplitudes than Na ⁺ APs.