ß2-Adrenergic Regulation of the Neuromuscular Transmission and Its Lipid-Dependent Switch.

Gafurova, Chulpan R; Tsentsevitsky, Andrei N; Fedorov, Nikita S; Khaziev, Arthur N; Malomouzh, Artem I; Petrov, Alexey M

Gafurova, Chulpan R; Tsentsevitsky, Andrei N; Fedorov, Nikita S; Khaziev, Arthur N; Malomouzh, Artem I; Petrov, Alexey M.

Afiliación

Gafurova CR; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St., Kazan, RT, Russia, 420111.
Tsentsevitsky AN; Kazan State Medical University, 49 Butlerova St., Kazan, RT, Russia, 420012.
Fedorov NS; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St., Kazan, RT, Russia, 420111.
Khaziev AN; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St., Kazan, RT, Russia, 420111.
Malomouzh AI; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St., Kazan, RT, Russia, 420111.
Petrov AM; Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center of RAS, 2/31 Lobachevsky St., Kazan, RT, Russia, 420111.

Mol Neurobiol ; 61(9): 6805-6821, 2024 Sep.

Article en En | MEDLINE | ID: mdl-38353924

ABSTRACT

ABSTRACT

ß2-Adrenoceptors (ß2-ARs) are the most abundant subtype of adrenergic receptors in skeletal muscles. Their activation via a stabilization of postsynaptic architecture has beneficial effects in certain models of neuromuscular disorders. However, the ability of ß2-ARs to regulate neuromuscular transmission at the presynaptic level is poorly understood. Using electrophysiological recordings and fluorescent FM dyes, we found that ß2-AR activation with fenoterol enhanced an involvement of synaptic vesicles in exocytosis and neurotransmitter release during intense activity at the neuromuscular junctions of mouse diaphragm. This was accompanied by an improvement of contractile responses to phrenic nerve stimulation (but not direct stimulation of the muscle fibers) at moderate-to-high frequencies. ß2-ARs mainly reside in lipid microdomains enriched with cholesterol and sphingomyelin. The latter is hydrolyzed by sphingomyelinases, whose upregulation occurs in many conditions characterized by muscle atrophy and sympathetic nerve hyperactivity. Sphingomyelinase treatment reversed the effects of ß2-AR agonist on the neurotransmitter release and synaptic vesicle recruitment to the exocytosis during intense activity. Inhibition of Gi protein with pertussis toxin completely prevented the sphingomyelinase-mediated inversion in the ß2-AR agonist action. Note that lipid raft disrupting enzyme cholesterol oxidase had the same effect on ß2-AR agonist-mediated changes in neurotransmission as sphingomyelinase. Thus, ß2-AR agonist fenoterol augmented recruitment and release of synaptic vesicles during intense activity in the diaphragm neuromuscular junctions. Sphingomyelin hydrolysis inversed the effects of ß2-AR agonist on neurotransmission probably via switching to Gi protein-dependent signaling. This phenomenon may reflect a dependence of the ß2-AR signaling on lipid raft integrity in the neuromuscular junctions.

Asunto(s)

Unión Neuromuscular; Receptores Adrenérgicos beta 2; Transmisión Sináptica; Animales; Unión Neuromuscular/efectos de los fármacos; Unión Neuromuscular/metabolismo; Transmisión Sináptica/efectos de los fármacos; Receptores Adrenérgicos beta 2/metabolismo; Microdominios de Membrana/metabolismo; Microdominios de Membrana/efectos de los fármacos; Ratones; Masculino; Diafragma/efectos de los fármacos; Diafragma/inervación; Diafragma/metabolismo; Esfingomielina Fosfodiesterasa/metabolismo; Vesículas Sinápticas/metabolismo; Vesículas Sinápticas/efectos de los fármacos; Colesterol/metabolismo; Exocitosis/efectos de los fármacos; Ratones Endogámicos C57BL

Palabras clave

Gi protein; Neuromuscular junction; Neurotransmitter release; Sphingomyelinase; Synaptic vesicle exocytosis; ß2-Adrenoceptor

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Adrenérgicos beta 2 / Transmisión Sináptica / Unión Neuromuscular Límite: Animals Idioma: En Revista: Mol Neurobiol Asunto de la revista: BIOLOGIA MOLECULAR / NEUROLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos

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