In: Nicotinic Acetylcholine Receptor Signaling in Neuroprotection [Internet]. Singapore: Springer; 2018. Chapter 1.


The nicotinic acetylcholine receptor (nAChR) is a typical ion channel type receptor. nAChR agonists such as nicotine evoke rapid excitatory responses in order of milliseconds. In addition to acute responses, sustained stimulation of nAChRs induces delayed cellular responses leading to neuroprotection via intracellular signal pathways probably triggered by Ca2+ influx. The most predominant subtypes of nAChRs expressed in the central nervous system (CNS) are α4 (known as α4β2) and α7 nAChRs. Long-term exposure to nicotine or acetylcholinesterase (AChE) inhibitors exerts protection against neurotoxicity induced by glutamate, β-amyloid, and other toxic insults. Nicotinic neuroprotection is mediated by α7 nAChR which shows high Ca2+ permeability, though contribution of α4 nAChR to nicotinic neuroprotection has also been suggested. Agonist stimulation of these receptors leads to activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, downstream of neurotrophin receptors. AChE inhibitors including donepezil which is used for treatment of Alzheimer’s disease, also activate PI3K-Akt pathway via nAChRs. Neuroprotective effects induced by long-term nAChR stimulation indicate that CNS nAChRs play important roles in promotion of neuronal survival under pathophysiological conditions such as brain ischemia and neurodegenerative diseases. Elucidation of neuroprotective mechanisms of nAChRs may enable development of novel therapies for neurodegenerative diseases.

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