دورية أكاديمية
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BDNF/TrkB signalling, in cooperation with muscarinic signalling, retrogradely regulates PKA pathway to phosphorylate SNAP-25 and Synapsin-1 at the neuromuscular junction.

التفاصيل البيبلوغرافية
العنوان: BDNF/TrkB signalling, in cooperation with muscarinic signalling, retrogradely regulates PKA pathway to phosphorylate SNAP-25 and Synapsin-1 at the neuromuscular junction.
المؤلفون: Polishchuk A; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Cilleros-Mañé V; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Balanyà-Segura M; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Just-Borràs L; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Forniés-Mariné A; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain., Silvera-Simón C; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Tomàs M; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Jami El Hirchi M; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Hurtado E; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Tomàs J; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain., Lanuza MA; Universitat Rovira i Virgili. Unitat d'Histologia i Neurobiologia (UHNeurob), Facultat de Medicina i Ciències de la Salut. c/ Sant Llorenç 21, Reus, 43201, Spain. mariaangel.lanuza@urv.cat.; Unitat d'Histologia i Neurobiologia (UHNeurob), Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain. mariaangel.lanuza@urv.cat.
المصدر: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Jul 23; Vol. 22 (1), pp. 371. Date of Electronic Publication: 2024 Jul 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : BioMed Central, c2003-
مواضيع طبية MeSH: Synapsins*/metabolism , Brain-Derived Neurotrophic Factor*/metabolism , Cyclic AMP-Dependent Protein Kinases*/metabolism , Neuromuscular Junction*/metabolism , Signal Transduction* , Receptor, trkB*/metabolism , Synaptosomal-Associated Protein 25*/metabolism, Animals ; Phosphorylation ; Rats ; Male ; Rats, Wistar ; Receptors, Muscarinic/metabolism
مستخلص: Background: Protein kinase A (PKA) enhances neurotransmission at the neuromuscular junction (NMJ), which is retrogradely regulated by nerve-induced muscle contraction to promote Acetylcholine (ACh) release through the phosphorylation of molecules involved in synaptic vesicle exocytosis (SNAP-25 and Synapsin-1). However, the molecular mechanism of the retrograde regulation of PKA subunits and its targets by BDNF/TrkB pathway and muscarinic signalling has not been demonstrated until now. At the NMJ, retrograde control is mainly associated with BDNF/TrkB signalling as muscle contraction enhances BDNF levels and controls specific kinases involved in the neurotransmission. Neurotransmission at the NMJ is also highly modulated by muscarinic receptors M 1 and M 2 (mAChRs), which are related to PKA and TrkB signallings. Here, we investigated the hypothesis that TrkB, in cooperation with mAChRs, regulates the activity-dependent dynamics of PKA subunits to phosphorylate SNAP-25 and Synapsin-1.
Methods: To explore this, we stimulated the rat phrenic nerve at 1Hz (30 minutes), with or without subsequent contraction (abolished by µ-conotoxin GIIIB). Pharmacological treatments were conducted with the anti-TrkB antibody clone 47/TrkB for TrkB inhibition and exogenous h-BDNF; muscarinic inhibition with Pirenzepine-dihydrochloride and Methoctramine-tetrahydrochloride for M 1 and M 2 mAChRs, respectively. Diaphragm protein levels and phosphorylation' changes were detected by Western blotting. Location of the target proteins was demonstrated using immunohistochemistry.
Results: While TrkB does not directly impact the levels of PKA catalytic subunits Cα and Cβ, it regulates PKA regulatory subunits RIα and RIIβ, facilitating the phosphorylation of critical exocytotic targets such as SNAP-25 and Synapsin-1. Furthermore, the muscarinic receptors pathway maintains a delicate balance in this regulatory process. These findings explain the dynamic interplay of PKA subunits influenced by BDNF/TrkB signalling, M 1 and M 2 mAChRs pathways, that are differently regulated by pre- and postsynaptic activity, demonstrating the specific roles of the BDNF/TrkB and muscarinic receptors pathway in retrograde regulation.
Conclusion: This complex molecular interplay has the relevance of interrelating two fundamental pathways in PKA-synaptic modulation: one retrograde (neurotrophic) and the other autocrine (muscarinic). This deepens the fundamental understanding of neuromuscular physiology of neurotransmission that gives plasticity to synapses and holds the potential for identifying therapeutic strategies in conditions characterized by impaired neuromuscular communication.
(© 2024. The Author(s).)
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فهرسة مساهمة: Keywords: Acetylcholine release; BDNF; Motor endplate; Muscarinic receptors; PKA; Serine kinases; TrkB
المشرفين على المادة: 0 (Synapsins)
0 (Brain-Derived Neurotrophic Factor)
EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
EC 2.7.10.1 (Receptor, trkB)
0 (Synaptosomal-Associated Protein 25)
0 (Receptors, Muscarinic)
0 (Bdnf protein, rat)
تواريخ الأحداث: Date Created: 20240723 Date Completed: 20240724 Latest Revision: 20240727
رمز التحديث: 20240727
مُعرف محوري في PubMed: PMC11265447
DOI: 10.1186/s12964-024-01735-2
PMID: 39044222
قاعدة البيانات: MEDLINE
الوصف
تدمد:1478-811X
DOI:10.1186/s12964-024-01735-2