M
            <sub>1</sub>
            and M
            <sub>2</sub>
            mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ

Cilleros-Mañé, Víctor; Just-Borràs, Laia; Полищук, А. А.; Durán, Maria Antònia; Tomàs, Marta; García, Neus; Tomàs, Josep; Lanuza, María A.

doi:10.1096/fj.202002213r

Cited by 9 publications

(12 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary antibodies were omitted from some samples during the procedure as controls, and they never revealed bands of the expected molecular weight. Furthermore, their specificity has been proved in previous publications from the group ( Obis et al, 2015b ; Hurtado et al, 2017a , b ; Simó et al, 2018 , 2019 ; Cilleros-Mañé et al, 2020 , 2021 ).…”

Section: Methodsmentioning

confidence: 59%

“… Graphical abstract showing the differential molecular features of fatigue resistant muscles [soleus (SOL) and extraocular muscles (EOM)] in comparison with fatigable muscles [extensor digitorum longus (EDL) and tibialis anterior (TA)]. Following the circular relation between the presynaptic and postsynaptic components of the neuromuscular junction (NMJ) gray arrow characterized by previous work done in Sprague Dawley rat diaphragms stimulated through the phrenic nerve ex vivo and activating or inhibiting each one of the proteins in the pathway ( Obis et al, 2015a , b ; Hurtado et al, 2017a , b ; Simó et al, 2018 , 2019 ; Cilleros-Mañé et al, 2020 , 2021 ), one can identify that muscular resistance to fatigue is mediated by constant neurotrophic consumption that modulates tropomyosin receptor kinase B (TrkB) phosphorylation ratio. Consequently, PKC activity in both SOL and EOM muscles is modified, which results in a differential balance of synaptic protein phosphorylation between fatigable and fatigue resistant muscles.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration

Just-Borràs

Cilleros-Mañé²,

Полищук³

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

At the neuromuscular junction (NMJ), motor neurons and myocytes maintain a bidirectional communication that guarantees adequate functionality. Thus, motor neurons’ firing pattern, which is influenced by retrograde muscle-derived neurotrophic factors, modulates myocyte contractibility. Myocytes can be fast-twitch fibers and become easily fatigued or slow-twitch fibers and resistant to fatigue. Extraocular muscles (EOM) show mixed properties that guarantee fast contraction speed and resistance to fatigue and the degeneration caused by Amyotrophic lateral sclerosis (ALS) disease. The TrkB signaling is an activity-dependent pathway implicated in the NMJ well-functioning. Therefore, it could mediate the differences between fast and slow myocytes’ resistance to fatigue. The present study elucidates a specific protein expression profile concerning the TrkB signaling that correlates with higher resistance to fatigue and better neuroprotective capacity through time. The results unveil that Extra-ocular muscles (EOM) express lower levels of NT-4 that extend TrkB signaling, differential PKC expression, and a higher abundance of phosphorylated synaptic proteins that correlate with continuous neurotransmission requirements. Furthermore, common molecular features between EOM and slow soleus muscles including higher neurotrophic consumption and classic and novel PKC isoforms balance correlate with better preservation of these two muscles in ALS. Altogether, higher resistance of Soleus and EOM to fatigue and ALS seems to be associated with specific protein levels concerning the TrkB neurotrophic signaling.

show abstract

Section: Methodsmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration

Just-Borràs

Cilleros-Mañé²,

Полищук³

et al. 2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…In contrast, M2 downregulated PKCε through a PKA-dependent pathway, which caused the inhibition of Munc18-1 synthesis and PKC phosphorylation. These results show the existence of a balance between mAChRs, which can regulate the presynaptic PKC and their action on ACh release through the SNARE-SM mechanism [ 67 ] or L-type Ca 2+ channels–PKC ensemble [ 63 ]. Thus, there are complex mAChR-dependent mechanisms that can change not only a number of ACh quanta released but modulate the time course of the secretion.…”

Section: Possible Mechanisms For Modulation Of the Kinetics Of Quanta...mentioning

confidence: 99%

Presynaptic Acetylcholine Receptors Modulate the Time Course of Action Potential-Evoked Acetylcholine Quanta Secretion at Neuromuscular Junctions

et al. 2022

View full text Add to dashboard Cite

For effective transmission of excitation in neuromuscular junctions, the postsynaptic response amplitude must exceed a critical level of depolarization to trigger action potential spreading along the muscle-fiber membrane. At the presynaptic level, the end-plate potential amplitude depends not only on the acetylcholine quanta number released from the nerve terminals in response to the nerve impulse but also on a degree of synchronicity of quanta releases. The time course of stimulus-phasic synchronous quanta secretion is modulated by many extra- and intracellular factors. One of the pathways to regulate the neurosecretion kinetics of acetylcholine quanta is an activation of presynaptic autoreceptors. This review discusses the contribution of acetylcholine presynaptic receptors to the control of the kinetics of evoked acetylcholine release from nerve terminals at the neuromuscular junctions. The timing characteristics of neurotransmitter release is nowadays considered an essential factor determining the plasticity and efficacy of synaptic transmission.

show abstract

“…In recent years, we have studied by immunohistochemistry, intracellular recording electrophysiology, western blotting, subcellular fractionation and co-immunoprecipitation, the involvement of the mAChR subtypes in the mammalian NMJ functionality during development and in the adult [3,[56][57][58][59][60][61]. In the adult, we characterized how M 1 and M 2 mAChRs regulate the PKA subunits (catalytic and regulatory), the PKC (PKCβI and ε isoforms), and their exocytotic targets (Munc18-1, SNAP-25, and MARCKS phosphorylation) showing a codependent balance between muscarinic auto receptors which orchestrates transmitter release regulation [62,63]. We analysed also the involvement of altered metabotropic receptor signaling in amyotrophic lateral sclerosis SOD1-G93A mice [64].…”

Section: Introductionmentioning

confidence: 99%

Muscarinic Receptors in Developmental Axonal Competition at the Neuromuscular Junction

et al. 2022

Self Cite

View full text Add to dashboard Cite

In recent years, we have studied by immunohistochemistry, intracellular recording, and western blotting the role of the muscarinic acetylcholine receptors (mAChRs; M1, M2, and M4 subtypes) in the mammalian neuromuscular junction (NMJ) during development and in the adult. Here, we evaluate our published data to emphasize the mAChRs’ relevance in developmental synaptic elimination and their crosstalk with other metabotropic receptors, downstream kinases, and voltage-gated calcium channels (VGCCs). The presence of mAChRs in the presynaptic membrane of motor nerve terminals allows an autocrine mechanism in which the secreted acetylcholine influences the cell itself in feedback. mAChR subtypes are coupled to different downstream pathways, so their feedback can move in a broad range between positive and negative. Moreover, mAChRs allow direct activity-dependent interaction through ACh release between the multiple competing axons during development. Additional regulation from pre- and postsynaptic sites (including neurotrophic retrograde control), the agonistic and antagonistic contributions of adenosine receptors (AR; A1 and A2A), and the tropomyosin-related kinase B receptor (TrkB) cooperate with mAChRs in the axonal competitive interactions which lead to supernumerary synapse elimination that achieves the optimized monoinnervation of musculoskeletal cells. The metabotropic receptor-driven balance between downstream PKA and PKC activities, coupled to developmentally regulated VGCC, explains much of how nerve terminals with different activities finally progress to their withdrawal or strengthening.

show abstract

M ₁ and M ₂ mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 9 publications

References 88 publications

TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration

TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration

Presynaptic Acetylcholine Receptors Modulate the Time Course of Action Potential-Evoked Acetylcholine Quanta Secretion at Neuromuscular Junctions

Muscarinic Receptors in Developmental Axonal Competition at the Neuromuscular Junction

Contact Info

Product

Resources

About

M 1 and M 2 mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 9 publications

References 88 publications

TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration

TrkB signaling is correlated with muscular fatigue resistance and less vulnerability to neurodegeneration

Presynaptic Acetylcholine Receptors Modulate the Time Course of Action Potential-Evoked Acetylcholine Quanta Secretion at Neuromuscular Junctions

Muscarinic Receptors in Developmental Axonal Competition at the Neuromuscular Junction

Contact Info

Product

Resources

About

M ₁ and M ₂ mAChRs activate PDK1 and regulate PKC βI and ε and the exocytotic apparatus at the NMJ