Modulation of M4 muscarinic acetylcholine receptors by interacting proteins

Abstract

Protein-protein interactions represent an important mechanism for posttranslational modifications of protein expression and function. In brain cells, surface-expressed and membrane-bound neurotransmitter receptors are common proteins that undergo dynamic protein-protein interactions between their intracellular domains and submembranous regulatory proteins. Recently, the Gαi/o-coupled muscarinic M4 receptor (M4R) has been revealed to be one of these receptors. Through direct interaction with the intracellular loops or C-terminal tails of M4Rs, M4R interacting proteins (M4RIPs) vigorously regulate the efficacy of M4R signaling. A synapse-enriched protein kinase, Ca2+/calmodulin-dependent protein kinase II (CaMKII), exemplifies a prototype model of M4RIPs, and is capable of binding to the second intracellular loop of M4Rs. Through an activity- and phosphorylation-dependent mechanism, CaMKII potentiates the M4R/Gαi/o-mediated inhibition of M4R efficacy in inhibiting adenylyl cyclase and cAMP production. In striatal neurons where M4Rs are most abundantly expressed, M4RIPs dynamically control M4R activity to maintain a proper cholinergic tone in these neurons. This is critical for maintaining the acetylcholine-dopamine balance in the basal ganglia, which determines the behavioral responsiveness to dopamine stimulation by psychostimulants.

Striatal, Hippocampal, and Cortical Networks Are Differentially Responsive to the M4- and M1-Muscarinic Acetylcholine Receptor Mediated Effects of Xanomeline

“…Activation of the Gq-coupled M1 receptor is typically expected to increase pCREB levels through calcium-dependent activation of PKC signaling pathways . By contrast, activation of the Gi/o-coupled M4 receptors is expected to decrease pCREB levels by reducing cAMP production . Surprisingly, we found that xanomeline produced differential pCREB responses in all three brain regions under investigation (Figure A).…”

Impaired Hippocampus-Dependent and Facilitated Striatum-Dependent Behaviors in Mice Lacking the Delta Opioid Receptor

“…Our gene expression analysis reveals potential molecular abnormalities in both striatonigral and striatopallidal pathways. On one hand, low mRNA levels of Camk2a and chrm4 (coding for the alpha isoform of the calcium/calmodulin-dependent protein kinase II-a critical effector of muscarinic receptor 4-and the cholinergic muscarinic receptor 4, respectively), and high mRNA levels of grin2b (NR2B subunit of NMDA glutamate receptors) may potentiate the striatonigral output (Gomeza et al, 1999;Guo et al, 2010;Jocoy et al, 2011;Tzavara et al, 2004). On the other hand, increased expression of Grm4 (metabotropic glutamate receptors mGluR4) and Pdyn (dynorphin and related peptides), and decreased expression of Tac1 (substance P) and Gpr6 (Gprotein-coupled receptor GPR6) would rather blunt striatopallidal activity (Govindaiah et al, 2010;Hopkins et al, 2009;Lobo et al, 2007;Perreault et al, 2007).…”

Delta Opioid Receptors: Learning and Motivation

“…Interestingly, transcriptional regulations of several genes in the CPu were coherent with behavioral data pointing to facilitated D1R-and blunted D2R-bearing MSN activity in DOR null mice. Indeed, low mRNA levels of Camk2 and chrm4 (coding for the alpha isoform of the calcium/calmodulin-dependent protein kinase II and mAchR4, respectively) and high mRNA levels of grin2b (NR2B subunit of NMDA glutamate receptors) could facilitatestriatonigral outputs in mutants (Gomeza et al 1999;Guo et al 2010;Jocoy et al 2011;Tzavara et al 2004). In contrast, increased expression of Grm4 (metabotropic glutamate receptor mGluR4) and Pdyn (prodynorphin) and decreased expression of Tac1 (substance P) and Gpr6 (GPR6) would rather inhibitstriatopallidal activity (Govindaiah et al 2010;Hopkins et al 2009;Lobo et al 2007;Perreault et al 2007).…”