Nicotinic Receptor: Molecular and Functional Aspects
Nicotinic receptors (nAChRs) are a family of ligand-gated ion channels (LGICs) that mediate neuronal and neuromuscular signal transduction. They are primarily activated by the neurotransmitter acetylcholine (ACh) and are localized at the neuromuscular junction (NMJ) and in the brain. The structure and function of nAChRs are critical for understanding the physiology and pathology of the nervous system. In this review, we will discuss the molecular and functional aspects of nAChRs, their roles in synaptic transmission, and their modulation by drugs and disease.
Structure
nAChRs are composed of five subunits, each of which is encoded by a different gene. The subunits form a pentameric structure with a central pore that opens in response to ACh binding. The subunits are divided into two classes based on their sequence homology and functional properties. The α-bungarotoxin-sensitive subunits (α4, α5, α6, β2, and β4) are sensitive to the snake venom toxin α-bungarotoxin and have higher ACh affinity than the non-α-bungarotoxin-sensitive subunits (α1, α2, α3, β1, and β3). All subunits contain a transmembrane domain with four transmembrane-spanning segments (M1-M4) and two extracellular loops (EL1 and EL2).
Function
nAChRs are ligand-gated ion channels that are activated by ACh binding to the extracellular domains of the subunits. Upon activation, the receptor opens to allow the passage of ions across the cell membrane. The major ions that are transported through the channel pore are Na+ and K+. This ion flux leads to a change in membrane potential that triggers the release of other neurotransmitters and the propagation of the signal along the axon.
nAChRs are located at the NMJ, where they are responsible for mediating the transmission of signals from motor neurons to skeletal muscle. At the NMJ, nAChRs are clustered in the postsynaptic membrane of the muscle fiber and respond to ACh released from the presynaptic nerve terminal. Upon activation, the nAChRs open and allow the influx of Na+ and K+ ions, resulting in a depolarization of the muscle fiber and initiating the contraction of the muscle.
In the brain, nAChRs are located in the presynaptic terminals of neurons, where they mediate the release of other neurotransmitters such as glutamate and GABA. They are also found in the postsynaptic membranes of neurons, where they modulate the synaptic transmission of signals from other neurons.
Modulation by Drugs and Disease
nAChRs can be modulated by drugs and disease. Some drugs, such as nicotine, act on nAChRs to either enhance or inhibit synaptic transmission. Nicotine binds to and activates the α4β2 subtype of nAChRs, resulting in an increase in the release of the neurotransmitter dopamine. This increase in dopamine leads to the pleasurable effects associated with smoking.
In addition, nAChRs are also modulated by disease. For example, mutations in the genes encoding the nAChR subunits have been linked to a number of neurological diseases, including myasthenia gravis and Alzheimer’s disease.
Conclusion
nAChRs are a family of ligand-gated ion channels that are critical for the regulation of neuronal and neuromuscular signal transduction. They are found at the NMJ and in the brain, where they are involved in the release of neurotransmitters and the modulation of synaptic transmission. nAChRs can be modulated by drugs and disease, and understanding their structure and function is essential for understanding the physiology and pathology of the nervous system.
References
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Gotti, C., & Clementi, F. (2009). Nicotinic acetylcholine receptors: From structure to function. Physiol. Rev., 89(3), 517–681. https://doi.org/10.1152/physrev.00020.2008
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