title: Increase of ryanodine receptors by dopamine D1 receptors is negatively regulated by γ-aminobutyric acid type B receptors in primary cultures of mouse cerebral cortical neurons.
abstract: Although upregulation of ryanodine receptor (RyR)-1 and -2 is mediated through the activation of dopamine D1 receptors (D1DRs) in the development of psychostimulant-induced place preference, little is known about how such increased expressions of RyRs are negatively regulated. This study investigated negative regulatory mechanisms of increase of RyR-1 and -2 expression by D1DR stimulation with its full agonist, SKF82958 or A 68930, using cultures of mouse cerebral cortical neurons. Sustained exposure to SKF82958 or A 68930 of the neurons increased RyR-1 and -2 proteins in a dose- and time-dependent-manner. The SKF82958-induced increases of RyR-1 and -2 proteins were significantly suppressed by SCH23390 (a selective D1DR antagonist). In addition, the SKF82958- or A 68930-induced increases of RyR-1 and -2 proteins were completely abolished by baclofen (a selective γ-aminobutyric acid type B [GABA(B)] receptor agonist), whereas muscimol (an agonist specific to GABA(A) receptors) had no effect. SKF82958 or A 68930 significantly increased intracellular cAMP level, which was completely suppressed by baclofen. Furthermore, sustained exposure to phorbol 12,13-dibutyrate, a protein kinase C activator, did not change the expression of RyR-1 or -2 proteins. Immunohistochemical study showed colocalizaton of immunoreactivities for three types of proteins, D1DRs and GABA(B) receptor R1 and R2 subunits in the same neuronal bodies, suggesting that the neurochemical changes induced by the activation of D1DRs and GABA(B) receptors occur in the same neurons. These results indicate that RyR-1 and -2 expression facilitated by D1DR stimulation are negatively regulated by GABA(B) receptor via suppression of cAMP production.
authors.affiliation: Department of Pharmacology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Koji
authors.initials: K
authors.lastname: Mizuno
authors.forename: Seitaro
authors.initials: S
authors.lastname: Ohkuma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018755:GABA Agonists; D017447:Receptors, Dopamine D1; D018080:Receptors, GABA-B; D019837:Ryanodine Receptor Calcium Release Channel; D000242:Cyclic AMP