Regulation of nicotinic acetylcholine receptors by tyrosine kinases in the peripheral and central nervous system: same players, different roles

Abstract

Nicotinic acetylcholine receptors (nAChRs) exist in many subtypes and are found in the peripheral and central nervous system where they mediate or modulate synaptic transmission. We review how tyrosine phosphorylation and kinases regulate muscle and neuronal nAChRs. Interestingly, although some of the same kinase players interact with the various receptor subtypes, the functional consequences are different. While concerted action of MuSK, Abl- and Src-family kinases (SFKs) regulates the synaptic distribution of nAChRs at the neuromuscular junction, SFKs activate heteromeric neuronal nAChRs in adrenal chromaffin cells, thereby enhancing catecholamine secretion. In contrast, the activity of homomeric neuronal nAChRs, as found in the hippocampus, is negatively regulated by tyrosine phosphorylation and SFKs. It appears that tyrosine kinases provide the means to regulate all nAChRs; but the functional consequences, even those caused by the same kinase family, are specific for each receptor subtype and location.

Na+/K+ ATPase regulates the expression and localization of acetylcholine receptors in a pump activity-independent manner

“…In our case, it is possible that the ad601 and/or ad467 mutations affect EAT-6 binding to the worm Src. nAchRs are also one of the target molecules of Src in the peripheral and central synapses of vertebrates (Wiesner and Fuhrer, 2006). Further biochemical analyses of the phosphorylation levels of the nAchRs in the eat-6 mutants will clarify the relationship between the distinct localization patterns of Na + /K + ATPase and the phosphorylation state of the nAchRs.…”

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

“…Various mechanisms have been proposed to explain nicotine-mediated up-regulation Buccafusco et al, 2009;Benowitz, 2010;Changeux, 2010b;Mao and McGehee, 2010). One hypothesis is that the initial receptor desensitization contributes to upregulation, possibly via receptor phosphorylation (Léna and Changeux, 1993;Swope et al, 1999;Wiesner and Fuhrer, 2006). More recently, it has been proposed that nicotine acts as a chaperone to promote maturation of ␣4 nAChR subunit precursors that might otherwise be degraded by currently unidentified endogenous molecular components (Sallette et al, 2005;Corringer et al, 2006;Tumkosit et al, 2006;Kuryatov et al, 2008;Walsh et al, 2008;Lester et al, 2009;Jones et al, 2010).…”

Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7

“…The phosphorylation and autophosphorylation of MuSK is thought to drive a downstream kinase signaling pathway that orchestrates and maintains the integrity of the neuromuscular junction. [23][24][25] Thus, a second possibility is that a downstream effect, from the stimulation of the ␤2-adrenergic receptors and subsequent activation of cAMP-protein kinase A, feeds into the MuSK signaling pathway at the neuromuscular junction. 26,27 This could partially compensate for the loss of MuSK signaling due to mutant Dok-7.…”