Author, as appears in the article.: Cilleros-Mane, V; Just-Borras, L; Polishchuk, A; Duran, M; Tomas, M; Garcia, N; Tomas, J M; Lanuza, M A
Department: Ciències Mèdiques Bàsiques
URV's Author/s: Cilleros Mañé, Víctor / DURAN ROMASEWSKYS, MARIA SOLEDAD / Garcia Sancho, Maria de les Neus / Just Borràs, Laia / Lanuza Escolano, María Angel / POLISHCHUK, ALEKSANDRA / Tomás Ferré, José Maria / Tomas Marginet, Marta
Keywords: Synaptosomal-associated protein 25 Synaptic transmission Snap-25 Signal transduction Receptors, muscarinic Rats, sprague-dawley Rats Protein-kinase-c Protein kinase c Presynaptic terminals Pkc Phosphorylation Pdpk1 protein, rat Pdk1 Neuromuscular junction Muscarinic receptors Exocytosis Down-regulation Animals Acetylcholine 3-phosphoinositide-dependent protein kinases transmitter release synaptosome-associated protein synaptic activity snap-25 possible involvement pkc pdk1 neurotransmitter release neuromuscular-junction neuromuscular junction muscarinic autoreceptors epidermal-growth-factor dependent phosphorylation
Abstract: Neuromuscular junctions (NMJ) regulate cholinergic exocytosis through the M1 and M2 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 M1 and M2 mAChR activates the master kinase PDK1 and promotes a particular priming of the presynaptic PKCβI and ε isoforms. M1 recruits both primed-PKCs to the membrane and promotes Munc18-1, SNAP-25, and MARCKS phosphorylation. In contrast, M2 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.
Thematic Areas: Saúde coletiva Química Psicología Odontología Nutrição Molecular biology Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Interdisciplinar Genetics General medicine Farmacia Engenharias iv Engenharias ii Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência de alimentos Cell biology Biotecnología Biotechnology Biology Biodiversidade Biochemistry & molecular biology Biochemistry Astronomia / física
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: aleksandra.polishchuk@urv.cat laia.just@urv.cat marta.tomas@urv.cat aleksandra.polishchuk@urv.cat victor.cilleros@alumni.urv.cat josepmaria.tomas@urv.cat laia.just@urv.cat mariaangel.lanuza@urv.cat
Author identifier: 0000-0001-6445-1538 0000-0003-0473-3730 0000-0002-4151-1697 0000-0001-6445-1538 0000-0001-5690-9932 0000-0002-0406-0006 0000-0003-0473-3730 0000-0003-4795-4103
Record's date: 2024-10-12
Journal volume: 35
Papper version: info:eu-repo/semantics/publishedVersion
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Faseb Journal. 35 (7): e21724-
APA: Cilleros-Mane, V; Just-Borras, L; Polishchuk, A; Duran, M; Tomas, M; Garcia, N; Tomas, J M; Lanuza, M A (2021). M1 and M2 mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ. Faseb Journal, 35(7), e21724-. DOI: 10.1096/fj.202002213R
Entity: Universitat Rovira i Virgili
Journal publication year: 2021
Publication Type: Journal Publications
Repositori URV