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mAChR
mAChRs are AChRs that form G-protein receptor complexes in the cell membranes of certain neurons and considered a potent target in the AD. It is evident that in CNS, muscarinic receptors are involved in memory, motor control and learning process. They play various roles such as acting as the primary end-receptor stimulated by ACh released from postganglionic neurons in the parasympathetic nervous system. It is reported that G-protein coupled M1 muscarinic receptor is impaired in the neocortex region of the patients with AD and severity of cognitive symptoms in the AD is greatly related to the degree of M1/G-protein uncoupling. Activation of M1 mAChRs also reduces tau hyperphosphorylation via glycogen synthase kinase-3b (GSK-3b) inhibition, increased ERK activation and potentiation of NMDA receptor. The neurotransmitter ACh binds to muscarine receptors (mAChR) that initiate a cascade of reactions involved in memory and cognition.
After activation of mAChR by ACh and mAChR agonist, PKC gets phosphorylated that results in phosphorylation of ERK1/2. A phosphorylated ERK1/2 activates a-secretase and c-secretase enzymes resulting in the nonamyloid processing of APP. a-secretase together with c-secretase cleaves the APP into soluble aAPP that is nonamyloidogenic in nature. Phosphorylation of PKC blocks the pathogenic amyloidogenic pathway that is possible by the activation of mAChR resulting from the association of the receptor and agonist. Phosphorylation of PKC also blocks GSK-3b resulting in decreased hyperphosphorylation of tau protein. Thus, for an increased nonamyloid pathway of APP, mAChR agonists are used for increased activation of a-secretase. As a matter of fact, activation of mAChRs also results in proliferation of neural progenitor cells in CNS.
References
1.Verma S,et al. J Pharm Pharmacol. 2018;70(8):985–993.
After activation of mAChR by ACh and mAChR agonist, PKC gets phosphorylated that results in phosphorylation of ERK1/2. A phosphorylated ERK1/2 activates a-secretase and c-secretase enzymes resulting in the nonamyloid processing of APP. a-secretase together with c-secretase cleaves the APP into soluble aAPP that is nonamyloidogenic in nature. Phosphorylation of PKC blocks the pathogenic amyloidogenic pathway that is possible by the activation of mAChR resulting from the association of the receptor and agonist. Phosphorylation of PKC also blocks GSK-3b resulting in decreased hyperphosphorylation of tau protein. Thus, for an increased nonamyloid pathway of APP, mAChR agonists are used for increased activation of a-secretase. As a matter of fact, activation of mAChRs also results in proliferation of neural progenitor cells in CNS.
References
1.Verma S,et al. J Pharm Pharmacol. 2018;70(8):985–993.
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