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THE PHARMA REVIEW (OCTOBER 2008)

Acetylcholine Receptor Channelopathies

Deepak Narang

Abstract: Nicotinic acetylcholine receptors (nAChRs) are a member of ligand-gated ion channels superfamily. nAChRs consist of non-selective cation channels responsible for ion flux across cell membrane. Acetylcholine by acting on nAChR regulates various cellular processes such as transmitter release, cell excitability, neuronal integration and influences physiological functions such as fatigue, anxiety, pain and cognitive functions. Mutations in these ion channels lead to pathological disease conditions such as congenital myasthenia gravis, autosomal dominant nocturnal frontal lobe epilepsy. In this review, nAChR ion channel, mutations in the ion channel leading to disease conditions and their mechanism will be focused.

Acetylcholine (ACh) is synthesised, stored and released by cholinergic neurons and transduce its signals by acting on muscarinic (mAChRs) and nicotinic acetylcholine receptors (nAChRs). nAChRs are present postsynaptically at the neuromuscular junction and peripheral autonomic ganglia and at presynaptic sites in the central nervous system (CNS). ACh by acting on nicotinic receptors mediates the end plate potential in muscle or an excitatory postsynaptic potential in peripheral ganglia. In CNS, it regulates processes such as transmitter release, cell excitability, neuronal integration and influence physiological functions such as fatigue, anxiety, pain and cognitive functions. nAChRs are pentameric ligand-gated ion channel receptors and constitute the ion channel with in the receptor. Dysfunctioning of nAChRs during development, adulthood or aging can lead to various diseases including muscle weakness, epilepsy, neurodegenerative disease, psychiatric disease, nicotine addiction etc. Myasthenia gravis, a neuromuscular disorder characterized by weakness and marked fatigability of skeletal muscle, is caused by an autoimmune response to the ACh receptor at the postjunctional endplate. However, congenital myasthenia gravis is a disorder (signs and symptoms similar to myasthenia gravis) occurring due to mutations in the nicotinic acetylcholine receptor at the neuromuscular junction which affect ligand binding and channel opening kinetics; Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an epileptic disorder which also occurs due to mutations in the presynaptic neuronal nAChR. In this review, nicotinic acetylcholine receptor mutations leading to channel disorders, their mechanisms and therapeutic options are discussed.

 

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