title: L-type voltage-dependent calcium channels facilitate acetylation of histone H3 through PKCγ phosphorylation in mice with methamphetamine-induced place preference.
abstract: The present study investigated regulation of histone acetylation by L-type voltage-dependent calcium channels (VDCCs), one of the machineries to provide Ca(2+) signals. Acetylation of histone through the phosphorylation of protein kinase Cγ (PKCγ) in the development of methamphetamine (METH)-induced place preference was demonstrated in the limbic forebrain predominantly but also in the nucleus accumbens of α1C subunit knockout mice. Chronic administration of METH produced a significant place preference in mice, which was dose-dependently inhibited by both chelerythrine (a PKC inhibitor) and nifedipine (an L-type VDCC blocker). Protein levels of acetylated histone H3 and p-PKCγ significantly increased in the limbic forebrain of mice showing METH-induced place preference, and it was also significantly attenuated by pre-treatment with chelerythrine or nifedipine. METH-induced place preference was also significantly attenuated by deletion of half the α1C gene, which is one of the subunits forming Ca(2+) channels. Furthermore, increased acetylation of histone H3 was found in specific gene-promoter regions related to synaptic plasticity, such as Nrxn, Syp, Dlg4, Gria1, Grin2a, Grin2b, Camk2a, Creb, and cyclin-dependent kinase 5, in wild-type mice showing METH-induced place preference, while such enhancement of multiple synaptic plasticity genes was significantly attenuated by a deletion of half the α1C gene. These findings suggest that L-type VDCCs play an important role in the development of METH-induced place preference by facilitating acetylation of histone H3 in association with enhanced expression of synaptic plasticity genes via PKCγ phosphorylation following an increase in the intracellular Ca(2+) concentration.
authors.affiliation: Department of Pharmacology, Kawa saki Medical School, Matsushima, Kurashiki, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Koji
authors.initials: K
authors.lastname: Mizuno
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Seitaro
authors.initials: S
authors.lastname: Ohkuma
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002843:Chromatin / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D047468:Immunoprecipitation; D007276:Injections, Intraventricular; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000378:metabolism; D010766:Phosphorylation; D016548:Prosencephalon / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D012054:Reinforcement, Psychology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D000697:Central Nervous System Stimulants; D002843:Chromatin; D006657:Histones; D008694:Methamphetamine; C087857:protein kinase C gamma; D011493:Protein Kinase C