This article describes the role of ion channels in neurophysiology and the disturbances that lead to neurologic disorders. Ion channels also act as targets for drug action. Examples of drugs targeted to ion channels for the treatment of neurologic disorders are given. Examples of epilepsy and neurodegenerative disorders are given to provide a glimpse into the impact of knowledge of ion channels on the future management of neurologic disorders.
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• Because ion channels are essential for a wide range of neural functions, their disturbance leads to several neurologic disorders.
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• The study of ion channels helps in understanding the pathomechanism of these diseases.
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• Identification of the receptors on ion channels and mutations of ion channel genes is providing targets for developing therapies for these disorders.
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• Channelopathies due to gain of function might respond to drugs blocking the action of those channels.
Historical note and terminology
Ion channels are protein pores in the cell membrane that allow the passage of ions down their respective electrochemical gradients. Ion channels are classified according to the ion passing through them (eg, sodium, potassium, calcium, or chloride), and the mechanisms by which they are opened or closed. Acetylcholine, for example, opens chloride channels. Channel blockers are molecules that can enter the pores and physically plug them.
The importance of ion channels in the generation and transmission of signals in the nervous system has been well recognized for over 60 years, since the classical work of Hodgkin and Huxley, in measurement of ion currents and conductance in sodium and potassium channels by classical voltage clamp techniques (18). These authors were awarded the Nobel Prize in 1963 for their concept of ion channels. Introduction of electrophysiological methods for the study of ion channels led to an explosion of research on ion channels in many different systems. The year 2016 marked the 50th anniversary of the first physiology studies, which demonstrated that glial cells rest at hyperpolarized resting membrane potentials relative to neurons and display large and selective permeability to K+ ions (22). A few years later, Bernard Katz showed that calcium was indispensable for the release of acetylcholine from the neuromuscular junction and, based on this work, shared the Nobel Prize for physiology and medicine with von Euler and Axelrod (21). In 1976 Neher and Sakmann demonstrated single channel current recording from ion channels (31). The Nobel Prize was awarded in 1991 to these authors for discovery of the patch clamp technique, which enabled the study of currents passing through single ion channels. In 1986 a complete sequence of cDNA coding of a sodium channel was published (32). The genes encoding several classes of ion channels have been cloned and sequenced during the past decade. Parallel to this, the number of human diseases resulting from mutations in the genes encoding ion channels has also increased.
Ion channels are essential for a wide range of cellular functions, including neuronal signaling, muscle contraction, sensory conduction, and endocrine secretions. Ion channels have a critical role in neurons because they enable the neurons to signal. It is to be expected that disturbances of ion channels and transporters would lead to disease. The first ion channel disorders were recognized in the skeletal muscle. Evidence for a defective chloride channel in myotonia congenita was presented in the 1970s, but it was not until 1994 that a mutation in the gene encoding the human skeletal muscle chloride channel was identified (26). These diseases are often called channelopathies, whereas those involving the nervous system are called neuronal channelopathies. This term does not include disturbances in ion channels seen in a large range of neurologic disorders, including trauma and cerebrovascular ischemia.
There are 2 basic types of ion channels, voltage-gated and ligand- or transmitter-gated, but some channels exhibit dual gating mechanisms. This article deals with the role of voltage-gated ion channels in the pathophysiology of neurologic diseases, and also with their role as targets for therapy. With the recognition of active glial participation in information processing, a physiological role for some of the glial channels and receptors is gradually emerging. Ion channels are expressed by astrocytes and oligodendrocytes as well as by Schwann cells.