ACh receptors are divided into two major classes, nicotinic ACh receptors (nAChRs) and muscarinic Ach receptors (mAChRs).  nAChRs are highly expressed in skeletal muscle and the nervous system.nAChRs are classified as members of the cysteine-loop (Cys-loop) family of ligandgated ion channels. Subtypes of nAChRs can be classified based on the predominant α-subunits (α1–α10) because the α subunit plays a key role in agonist binding to trigger ion channel opening, and subtype-selective antagonists like α-bungarotoxin distinguish receptors based on the α subunit combination. Recently, expression of nAChRs in immune cells and glial cells has also attracted attention for potential therapeutic targeting in inflammation and neurodegenerative diseases. nAChRs are grouped into muscle-type (Nm), peripheral neuronal-type (Nn), and central neuronal-type (CNS) based on their distribution, subunit composition, and selective antagonists. In all types of nAChRs, agonists such as ACh itself or nicotine-induced ion channel opening and evoke influx of Na+ and Ca2+. 
This triggers cell depolarization and turns on various functional switches. Nicotinic cholinergic responses correlated with fast neurotransmission are easily detected in the endplate at the neuromuscular junction and ganglion cells of the sympathetic nerves.  In the cerebral cortex, persistent nAChR stimulation triggers signals to the phosphoinositide 3-kinase (PI3K) cascade, which contributes to neuroprotection.  nAChRs, especially α7 nAChRs, generate specific and complex Ca2+ signals that include adenylyl cyclase, protein kinase A, protein kinase C, Ca2+-calmodulin-dependent kinase, and phosphatidylinositol 3-kinase (PI3K). These phosphorylated downstream targets activate cellular signaling related to exocytosis and extracellular signal-regulated mitogen-activated protein kinase (ERK)-linked neuronal functions. The intracellular signal pathway downstream of CNS nAChRs is known as a major pathway of neuroprotective action of neurotrophins including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). NGF and BDNF are known to affect survival and differentiation of central and peripheral neurons.


1.Akaike A, et al. Springer; 2018:1–15.