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M 1 and M 2 mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ
Author(s) -
CillerosMañé V.,
JustBorràs L.,
Polishchuk A.,
Durán M.,
Tomàs M.,
Garcia N.,
Tomàs J. M.,
Lanuza M. A.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002213r
Subject(s) - protein kinase c , microbiology and biotechnology , muscarinic acetylcholine receptor , autoreceptor , muscarine , neuromuscular junction , marcks , exocytosis , biology , acetylcholine receptor , phosphorylation , neuroscience , cholinergic , signal transduction , receptor , endocrinology , biochemistry , serotonin , secretion
Neuromuscular junctions (NMJ) regulate cholinergic exocytosis through the M 1 and M 2 muscarinic acetylcholine autoreceptors (mAChR), involving the crosstalk between receptors and downstream pathways. Protein kinase C (PKC) regulates neurotransmission but how it associates with the mAChRs remains unknown. Here, we investigate whether mAChRs recruit the classical PKCβI and the novel PKCε isoforms and modulate their priming by PDK1, translocation and activity on neurosecretion targets. We show that each M 1 and M 2 mAChR activates the master kinase PDK1 and promotes a particular priming of the presynaptic PKCβI and ε isoforms. M 1 recruits both primed‐PKCs to the membrane and promotes Munc18‐1, SNAP‐25, and MARCKS phosphorylation. In contrast, M 2 downregulates PKCε through a PKA‐dependent pathway, which inhibits Munc18‐1 synthesis and PKC phosphorylation. In summary, our results discover a co‐dependent balance between muscarinic autoreceptors which orchestrates the presynaptic PKC and their action on ACh release SNARE‐SM mechanism. Altogether, this molecular signaling explains previous functional studies at the NMJ and guide toward potential therapeutic targets.