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Drugs that act on the central nervous system (CNS) are the most commonly prescribed drugs in current use. Most of these drugs act by changing ion flow through transmembrane channels of nerve cells. Transmitter reuptake transporters constitute a second class of drug targets, especially for antidepressant agents. Inhibition of acetylcholine metabolism is the major action of the drugs currently approved for use in Alzheimer disease and γ-aminobutyric acid (GABA) metabolism is inhibited by an anticonvulsant agent. Finally, a few drugs appear to act by altering the function of neuroglia. These satellite cells have been shown to modulate transmitter synthesis and disposition and support neurons metabolically. Microglia have also been shown to “prune” neuronal networks in the normal development of the CNS and possibly in Alzheimer disease and schizophrenia.

A. Types of Ion Channels

Ion channels of neuronal membranes are of two major types: voltage gated and ligand gated (Figure 21–1). Voltage-gated ion channels respond to changes in membrane potential. They are found in high concentration on the axons of nerve cells and include the sodium channels responsible for action potential propagation. Cell bodies, axon terminals, and dendrites have voltage-sensitive ion channels for sodium, potassium, and calcium. Ligand-gated ion channels, also called ionotropic receptors, respond to chemical neurotransmitters that bind to receptor subunits present in their macromolecular structure. Neurotransmitters also bind to G-protein-coupled receptors (metabotropic receptors) that can modulate voltage-gated ion channels. Neurotransmitter-coupled ion channels are found on cell bodies and on both the presynaptic and postsynaptic sides of synapses.


Types of ion channels and neurotransmitter receptors in the CNS: A shows a voltage-gated ion channel in which the voltage sensor controls the gating (broken arrow). B shows a ligand-gated ion channel in which binding of the neurotransmitter to the ionotropic channel receptor controls the gating. C shows a metabotropic receptor coupled to a G protein that can interact directly with an ion channel. D shows a receptor coupled to a G protein that activates an enzyme; the activated enzyme generates a diffusible second messenger, for example, cAMP, which interacts to modulate an ion channel. (Reproduced with permission from Katzung BG, Vanderah TW: Basic & Clinical Pharmacology, 15th ed. New York, NY: McGraw Hill; 2021.)

B. Types of Receptor-Channel Coupling

In the case of ligand-gated ion channels, activation (or inhibition) is initiated by the interaction between chemical neurotransmitters and their receptors (Figure 21–1). Coupling may be through a receptor that acts directly on the channel protein (panel B), through a receptor that is coupled to the ion channel through a G protein (panel C), or through a receptor coupled to a G protein that modulates the formation of diffusible second messengers, including cyclic adenosine monophosphate (cAMP), inositol trisphosphate (IP3), ...

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