Regulation of Src family kinases by muscarinic acetylcholine receptors in heterologous cells and neurons

Abstract

Five muscarinic acetylcholine (mACh) receptor subtypes are divided into two classes: the M1 class (M₁, M₃, and M₅) and the M2 class (M₂ and M₄). The former is coupled to G_q proteins, while the latter is coupled to G_i/o proteins. Accumulating evidence indicates that mACh receptors play a significant role in the regulation of the Src family kinase (SFK), a subfamily of non-receptor tyrosine kinases. mACh receptors exert their roles in a subtype-dependent fashion and preferentially target Src and Fyn, two members of SFKs that are expressed in the brain and enriched at synaptic sites. While the M₁ receptor positively modulates SFK activity, the M₄ receptor inhibits it. By modulating SFKs, mACh receptors are actively involved in the regulation of expression and function of a variety of receptors, structural proteins, and signaling molecules. In particular, the M₄ receptor and the dopamine D₁ receptor are coexpressed in striatonigral projection neurons of the striatum. G_i/o-coupled M₄ and G_q-coupled D₁ receptors antagonistically regulate SFK activity, thereby forming a dynamic balance controlling glutamate receptor activity, excitability of neurons, and synaptic plasticity. In summary, mACh receptors play a crucial role in regulating SFK activity in heterologous cells and neurons.

Keywords: Fyn; M1 receptor; M4 receptor; Src; striatum; tyrosine kinase.