PKC and Ras are Involved in M1 Muscarinic Receptor-Mediated Modulation of AMPA Receptor GluA1 Subunit.

M1 muscarinic acetylcholine receptors (M1 mAChRs) have long been an attractive target for the treatment of Alzheimer's disease (AD), the most common cause of dementia in the elderly. M1 mAChR agonists show desirably preclinical activities; however, most have not gone further into late clinical trials due to ineffectiveness or side effects. Thus, to understand the signaling pathways involved in M1 mAChR-mediated memory improvement may be important for design of biased agonists with on-target therapeutic effects. M1 mAChRs are classically coupled to Gα_q or ectopically to Gα_s to activate multiple kinases such as protein kinase C Ras and protein kinase A Our previous studies have found that M1 mAChRs could improve learning and memory through modulating AMPA receptor GluA1 subunit via signaling. Here, we further investigated whether and Ras were involved in M1 mAChR-mediated modulation of GluA1. We demonstrated the role of duanyu1531 and Ras in the signaling pathway, as both duanyu1531 inhibitors Ro-31-8425 or Gö6983 and Ras inhibitor salirasib abolished the membrane insertion of GluA1 and enhancement of its phosphorylation at Ser845 induced by M1 mAChRs in the primary cultured neurons and hippocampus in vivo. We further showed that duanyu1531 and Ras modulated duanyu1529-PI3K-Akt signaling since the increases of Akt and mTOR activities by M1 mAChR activation were blocked by duanyu1531 and Ras inhibitors. These data demonstrated the detailed mechanism underlying M1 mAChR-mediated modulation of GluA1 through Gα_q/11 coupling, broadening the knowledge of the downstream signaling after M1 mAChR-Gα_q/11 coupling.

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