Articles producció científica> Ciències Mèdiques Bàsiques

M1 and M2 mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ

  • Datos identificativos

    Identificador: imarina:9219145
    Autores:
    Cilleros-Mane, VJust-Borras, LPolishchuk, ADuran, MTomas, MGarcia, NTomas, J MLanuza, M A
    Resumen:
    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.
  • Otros:

    Autor según el artículo: Cilleros-Mane, V; Just-Borras, L; Polishchuk, A; Duran, M; Tomas, M; Garcia, N; Tomas, J M; Lanuza, M A
    Departamento: Ciències Mèdiques Bàsiques
    Autor/es de la URV: 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
    Palabras clave: 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
    Resumen: 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.
    Áreas temáticas: 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
    Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/
    Direcció de correo del autor: 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
    Identificador del autor: 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
    Fecha de alta del registro: 2024-10-12
    Volumen de revista: 35
    Versión del articulo depositado: info:eu-repo/semantics/publishedVersion
    Enlace a la fuente original: https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202002213R
    URL Documento de licencia: https://repositori.urv.cat/ca/proteccio-de-dades/
    Referencia al articulo segun fuente origial: Faseb Journal. 35 (7): e21724-
    Referencia de l'ítem segons les normes 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
    DOI del artículo: 10.1096/fj.202002213R
    Entidad: Universitat Rovira i Virgili
    Año de publicación de la revista: 2021
    Tipo de publicación: Journal Publications
  • Palabras clave:

    Biochemistry,Biochemistry & Molecular Biology,Biology,Biotechnology,Cell Biology,Genetics,Medicine (Miscellaneous),Molecular Biology
    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
    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
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