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Diazepam-Induced Down-Regulation of the GABAA receptor α1 Subunit, as mediated by the activation of L-Type Voltage-Gated calcium Channel/Ca2+/Protein kinase a signaling cascade.
González Gómez, Leydi Carolina; Medina, Nelsy Beatriz; Sanz Blasco, Sara; Gravielle, María Clara.
Afiliação
  • González Gómez LC; Instituto de Investigaciones Farmacológicas (ININFA). Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires. CONICET. Buenos Aires, Argentina.
  • Medina NB; Instituto de Investigaciones Farmacológicas (ININFA). Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires. CONICET. Buenos Aires, Argentina.
  • Sanz Blasco S; Instituto de Investigaciones Farmacológicas (ININFA). Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires. CONICET. Buenos Aires, Argentina.
  • Gravielle MC; Instituto de Investigaciones Farmacológicas (ININFA). Facultad de Farmacia y Bioquímica. Universidad de Buenos Aires. CONICET. Buenos Aires, Argentina. Electronic address: graviell@ffyb.uba.ar.
Neurosci Lett ; 810: 137358, 2023 07 27.
Article em En | MEDLINE | ID: mdl-37356564
Benzodiazepines are among the most prescribed drug class worldwide to treat disorders such as anxiety, insomnia, muscle spasticity, and convulsive disorders, and to induce presurgical sedation. Although benzodiazepines exhibit a high therapeutic index and low toxicity in short-term treatments, prolonged administration induces tolerance to most of their therapeutic actions. The mechanism of this tolerance remains unclear. The central actions of benzodiazepines are mediated by binding to GABAA receptors, which mediate most fast inhibitory transmission in the brain. The majority of GABAA receptors are composed of two α-(1-6), two ß-(1-3) and one γ-subunits (1-3). In a previous report, we demonstrated that the prolonged exposure of cerebrocortical neurons to diazepam produces a transcriptional repression of the GABAA receptor α1 subunit gene via a mechanism dependent on the activation of L-type voltage-gated calcium channels (L-VGCCs). The results reported here confirm that the diazepam-induced downregulation of the α1 subunit is contingent upon calcium influx from extracellular space. In addition, this regulatory mechanism involves the activation of protein kinase A (PKA) and is accompanied by the activation of two transcription factors, the cAMP-response element-binding protein (CREB) and the inducible cAMP early repressor (ICER). Together, our results suggest that diazepam s activation of an L-VGCC/Ca2+/PKA/CREB-ICER signaling pathway is responsible for the regulation of GABAA receptors. This elucidation of the intracellular signaling cascade activated by a prolonged benzodiazepine exposure, itself potentially involved in the development of tolerance, may contribute to locating molecular targets for future therapeutic interventions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de GABA-A / Diazepam Idioma: En Revista: Neurosci Lett Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Argentina País de publicação: Irlanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de GABA-A / Diazepam Idioma: En Revista: Neurosci Lett Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Argentina País de publicação: Irlanda