Inhibition of basal and amphetamine-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in the rat forebrain by muscarinic acetylcholine M4 receptors

Abstract

The mitogen-activated protein kinase (MAPK), especially its extracellular signal-regulated kinase (ERK) subfamily, is a group of kinases enriched in the mammalian brain. While ERK is central to cell signaling and neural activities, the regulation of ERK by transmitters is poorly understood. In this study, the role of acetylcholine in the regulation of ERK was investigated in adult rat striatum in vivo. We focused on muscarinic M1 and M4 receptors, two principal muscarinic acetylcholine (mACh) receptor subtypes in the striatum. A systemic injection of the M1-preferring antagonist telenzepine did not alter ERK phosphorylation in the two subdivisions of the striatum, the caudate putamen and nucleus accumbens. Similarly, telenzepine did not affect ERK phosphorylation in the medial prefrontal cortex (mPFC), hippocampus, and cerebellum. Moreover, telenzepine had no effect on the ERK phosphorylation induced by dopamine stimulation with the psychostimulant amphetamine. In contrast to telenzepine, the M4-preferring antagonist tropicamide consistently increased ERK phosphorylation in the striatum and mPFC. This increase was rapid and transient. Tropicamide and amphetamine when coadministered at subthreshold doses induced a significant increase in ERK phosphorylation. These results demonstrate that mACh receptors exert a subtype-specific modulation of ERK in striatal and mPFC neurons. While the M1 receptor antagonist has no effect on ERK phosphorylation, M4 receptors inhibit constitutive and dopamine-stimulated ERK phosphorylation in these dopamine-innervated brain regions.

Striatal Dopamine Induced ERK Phosphorylation Is Altered in Mouse Models of Monogenic Dystonia

“…Interestingly, the anticholinergic trihexyphenidyl, used in patients, increases ERK phosphorylation in a mouse model of tauopathy, 81 whereas the muscarinic inhibitor atropine blocks ERK phosphorylation induced by carbachol 82 . Baseline and/or dopamine‐stimulated pERK is abnormal in the models studied herein, and both are inhibited by M4 receptors in these dopaminoceptive regions 83 . The M1 and M4 receptors are under investigation as therapeutic targets 9,56,57 …”

“…82 Baseline and/or dopamine-stimulated pERK is abnormal in the models studied herein, and both are inhibited by M4 receptors in these dopaminoceptive regions. 83 The M1 and M4 receptors are under investigation as therapeutic targets. 9,56,57…”

Novel Multitarget Directed Tacrine Hybrids as Anti-Alzheimer’s Compounds Improved Synaptic Plasticity and Cognitive Impairment in APP/PS1 Transgenic Mice

“…Noticeably, our results showed that 9i reduced the expression of Ras, MEK, and ERK proteins in APP/PS1 mice. Interestingly, the cholinergic system also plays a role in ERK activation. , Studies suggested that muscarinic acetylcholine receptors and nicotinic acetylcholine receptors are highly expressed in the striatum, prefrontal cortex, and hippocampus in mammalian brains, while M4 receptor blockers could up-regulate the phosphorylation of ERK1/2 under physiological conditions, − which suggested that regulating the cholinergic system inhibited the MEK/ERK signaling pathway to improve the cognitive function of AD mice.…”

Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

“…While M 1 , M 3 and M 5 predominantly couple to GPCR's via the G q protein alpha subunit (G q/11 ), M 2 and M 4 preferentially facilitate signal transduction though the G i and G o protein alpha subunits (G i/o ) 5 . Accordingly, the activation of M 2 and M 4 by ACh globally leads to an inhibition of adenylyl cyclase, followed by reduction of cyclic AMP (cAMP) formation 6 , 7 . Owing to the broad implications of M 4 receptors in central nervous system (CNS)-related pathologies, including Alzheimer's disease (AD) 8 , 9 , schizophrenia 10 , 11 and dementia with Lewy bodies (DLB) 12 , M 4 activation via synthetic agonists has proven to be of high therapeutic value.…”

“…Previous studies revealed that muscarinic M 4 receptors are markedly expressed in the mammalian brain, with high abundancies in the striatum, thalamus and cortex 15 , 16 , 17 , 18 . Notably, considerable species differences have been described for the localization and structure of M 4 7 , 19 , 20 , 21 , explaining the variability of binding affinities for some synthetic M 4 ligands across different species 22 , 24 . Strenuous drug development efforts prompted the discovery of several M 4 agonists, however, due to the high degree of structural homology among the orthosteric site of the different mAChR subtypes, the identification of an orthosteric M 4 -selective ligand has proven challenging 23 , 24 , 25 , 26 .…”