Rapid use-dependent down-regulation of gamma-aminobutyric acid type A receptors in rat mesencephalic trigeminal neurons.
Rundown is ubiquitously seen in response to repetitive activation of receptor or ion channels as a use-dependent down-regulation through various mechanisms. In contrast to AMPA receptors, gamma-aminobutyric acid type A receptor (GABA(A)R) are believed to display no rapid use-dependent down-regulation. We report here a rapid use-dependent down-regulation of GABA(A)R in primary sensory neurons of rat mesencephalic trigeminal nucleus (MTN), which express synaptic GABA(A)Rs in addition to extrasynaptic ones, unlike other primary sensory neurons. When muscimol was repetitively puff-applied to an MTN neuron every 2 min before, during, and after the muscimol bath application for 5 min, both the GABA(A) responses obtained under both current- and voltage-clamp conditions were almost completely depressed during the bath application. However, the former and latter GABA(A) responses recovered to 26% +/- 7% and 36% +/- 7% of their control amplitudes, respectively, 15 min after washout of the bath-applied muscimol. By contrast, when examined in the presence of chelerythrine, a protein kinase C (PKC) inhibitor, together with a stringent chelation of intracellular Ca(2+), the puff responses were almost completely recovered, whereas those were recovered to 40-60% of the control by either chelerythrine or EGTA alone. A phosphatidylinositol 3-kinase inhibitor (PI3K), wortmannin, which blocks various signal transductions, including vesicular trafficking, significantly enhanced the rundown of the puff responses examined every 2 min. These findings indicate that the rundown of GABA(A) response in MTN neurons is mediated by the use-dependent down-regulation of GABA(A)R, which is reversed by PKC inhibition together with intracellular Ca(2+) chelation, while being facilitated by PI3K inhibition.
Saito
Mitsuru
M
Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, Osaka, Japan.
Toyoda
Hiroki
H
Sato
Hajime
H
Ishii
Hisayoshi
H
Kang
Youngnam
Y
D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D018755:GABA Agonists / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D014278:Trigeminal Nuclei / Q000187:drug effects / Q000378:metabolism
D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; C016299:chelerythrine; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D002118:Calcium