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Channelopathies

Voltage-gated channels for sodium, potassium, calcium, and chloride are intimately associated with excitability in neurons and muscle cells and in synaptic transmission. Until the early 1990s, most of our knowledge about channel properties derived from biophysical studies of isolated cells or their membranes. The advent of molecular approaches resulted in the cloning of the genes for a variety of channels and the subsequent expression of these genes in a large cell, such as the Xenopus oocyte, for further characterization.

This approach also allowed experimental manipulation of the channels by expressing genes that were altered in known ways. In this way, researchers could determine which parts of channel molecules were responsible for particular properties, including voltage sensitivity, ion specificity, activation, inactivation, kinetics, and interaction with other cellular components. This genetic understanding of the control of channel properties led to the realization that many unexplained diseases may be caused by alterations in the genes for ion channels. Diseases based on altered ion channel function are now collectively called channelopathies. These diseases affect neurons, skeletal muscle, cardiac muscle, and even nonexcitable cells, such as kidney tubular cells.

One of the best-known sets of channelopathies is a group of channel mutations that lead to the Long Q-T (LQT) syndrome in the heart. The QT interval on the electrocardiogram is the time between the beginning of ventricular depolarization and the end of ventricular repolarization. In patients with LQT, the QT interval is abnormally long because of defective membrane repo-larization, which can lead to ventricular arrhythmia and sudden death. Affected individuals generally have no cardiovascular disease other than that associated with electrical abnormality. The defect in membrane repolar-ization could be a result of a prolonged inward sodium current or a reduced outward potassium current. In fact, mutations in potassium channels account for two different LQT syndromes, and a third derives from a sodium channel mutation.

Myotonia is a condition characterized by a delayed relaxation of muscle following contraction. There are several types of myotonias, all related to abnormalities in muscle membrane. Some myotonias are associated with a skeletal muscle sodium channel, and others are associated with a skeletal muscle chloride channel.

Channelopathies affecting neurons include episodic and spinocerebellar ataxias, some forms of epilepsy, and familial hemiplegic migraine. Ataxias are a disruption in gait mediated by abnormalities in the cerebellum and spinal motor neurons. One specific ataxia associated with an abnormal potassium channel is episodic ataxia with myokymia. In this disease, which is autosomal-dominant, cerebellar neurons have abnormal excitability and motor neurons are chronically hyperexcitable. This hyperex-citability causes indiscriminant firing of motor neurons, observed as the twitching of small groups of muscle fibers, akin to worms crawling under the skin (myokymia). It is likely that many other neuronal (and muscle) disorders of currently unknown pathology will be identified as chan-nelopathies.

when an action potential is generated in one region of the axon, more of the adjacent region that is depolarized by the inward current accompanying the action potential reaches the threshold for action potential generation. The result is that the speed at which action potentials are conducted, or conduction velocity, increases as a function of increasing axon diameter and concomitant increase in the space constant.

Several factors act to increase significantly the conduction velocity of action potentials in myelinated axons. Schwann cells in the PNS and oligodendrocytes in the CNS wrap themselves around axons to form myelin, layers of lipid membrane that insulate the axon and prevent the passage of ions through the axonal membrane (Fig. 3.6B). Between the myelinated segments of the axon are the nodes of Ranvier, where action potentials are generated.

The signal that causes these glial cells to myelinate the axons apparently derives from the axon, and its potency is a function of axon size. In general, axons larger than approximately 1 |xm in diameter are myelinated, and the thickness of the myelin increases as a function of axon diameter. Since the smallest myelinated axon is bigger than the largest unmyelinated axon, conduction velocity is faster for myelinated axons based on size alone. In addition, the myelin acts to increase the effective resistance of the axonal membrane, Rm, since ions that flow across the axonal membrane must also flow through the tightly wrapped layers of myelin before they reach the extracellular fluid. This increase in Rm increases the space constant. The layers of myelin also decrease the effective capacitance of the axonal membrane because the distance between the extracellular and intracellular conducting fluid compartments is increased. Because the capacitance is decreased, the time constant is decreased, increasing the conduction velocity.

While the effect of myelin on Rm and capacitance are important for increasing conduction velocity, there is an even greater factor at play—an alteration in the mode of conduction. In myelinated axons, voltage-gated Na+ channels are highly concentrated in the nodes of Ranvier, where the myelin sheath is absent, and are in low density beneath the segments of myelin. When an action potential is initiated at the axon hillock, the influx of Na+ ions causes the adjacent node of Ranvier to depolarize, resulting in an action potential at the node. This, in turn, causes depolarization of the next node of Ranvier and the eventual initiation of an action potential. Action potentials are successively generated at neighboring nodes of Ranvier; therefore, the action potential in a myelinated axon appears to jump from one node to the next, a process called saltatory conduction (Fig. 3.6C). This process results in a faster conduction velocity for myelinated than unmyelinated axons. The conduction velocity in mammals ranges from 3 to 120 m/sec for myelinated axons and 0.5 to 2.0 m/sec for unmyelinated axons.

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