Study, July/23: 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

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Diazepam-Induced Down-Regulation of the GABA_A receptor α1 Subunit, as mediated by the activation of L-Type Voltage-Gated calcium Channel/Ca²⁺/Protein kinase a signaling cascade

https://pubmed.ncbi.nlm.nih.gov/37356564/

 

Abstract

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 GABA_A receptors, which mediate most fast inhibitory transmission in the brain. The majority of GABA_A receptors are composed of two α-(1-6), two β-(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 GABA_A 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 GABA_A 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.