We have located links that may give you full text access.
Diazepam-Induced Down-Regulation of The Gaba a Receptor α1 Subunit, as Mediated by the Activation of L-Type Voltage-Gated Calcium Channel/Ca 2+ /Protein Kinase A Signaling Cascade.
Neuroscience Letters 2023 June 24
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 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 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.
Full text links
Related Resources
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app