ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Changes in GABA receptor (GABAAR) gene expression are detected in animal models of epilepsy, anxiety and in post-mortem schizophrenic brain, suggesting a role for GABAAR regulation in neurological disorders. Persistent (48 h) exposure of brain neurons in culture to GABA results in down-regulation of GABAAR number and uncoupling of GABA and benzodiazepine (BZD) binding sites. Given the central role of GABAARs in fast inhibitory synaptic transmission, GABAAR down-regulation and uncoupling are potentially important mechanisms of regulating neuronal excitability, yet the molecular mechanisms remain unknown. In this report we show that treatment of brain neurons in culture with tetrodotoxin, glutamate receptor antagonists, or depolarization with 25 mm K+ fails to alter GABAAR number or coupling. Changes in neuronal activity or membrane potential are therefore not sufficient to induce either GABAAR down-regulation or uncoupling. Nifedipine, a voltage-gated Ca2+ channel (VGCC) blocker, inhibits both GABA-induced increases in [Ca2+]i and GABAAR down-regulation, suggesting that VGCC activation is required for GABAAR down-regulation. Depolarization with 25 mm K+ produces a sustained increase in intracellular [Ca2+] without causing GABAAR down-regulation, suggesting that activation of VGCCs is not sufficient to produce GABAAR down-regulation. In contrast to GABAAR down-regulation, nifedipine and 25 mm K+ fail to inhibit GABA-induced uncoupling, demonstrating that GABA-induced GABAAR down-regulation and uncoupling are mediated by independent molecular events. Therefore, GABAAR activation initiates at least two distinct signal transduction pathways, one of which involves elevation of intracellular [Ca2+] through VGCCs.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2001.00501.x
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