title: Inhibition of L-type Ca(2+) channels by curcumin requires a novel protein kinase-theta isoform in rat hippocampal neurons.
abstract: Curcumin, a major active compound of Curcuma longa, has been reported to have potent neuroprotective activities. However to date, the relevant mechanisms still remain unclear. In this study, we report that curcumin selectively inhibits L-type Ca(2+) channel currents in cultured rat hippocampal neurons. Whole-cell currents were recorded using 10mM barium as a charge carrier. Curcumin reversibly inhibited high-voltage-gated Ca(2+) channel (HVGCC) currents (IBa) in a concentration-dependent manner but had no apparent effects on the cells treated with nifedipine, a specific L-type Ca(2+) channel blocker. Curcumin did not markedly affect the activation of L-type Ca(2+) channels while significantly shifted the inactivation curve in the hyperpolarizing direction. Pretreatment of cells with the classical and novel PKC antagonists GF109203X and calphostin C completely abolished curcumin-induced IBa inhibition, whereas the classical PKC antagonist Gö6976 or inhibition of PKA activity elicited no such effects. Moreover, the curcumin-induced IBa response was abolished by intracellular application of the PKC-θ inhibitory peptide PKC-θ-IP or by siRNA knockdown of PKC-θ in cultured rat hippocampal neurons. In these neurons, novel isoforms of PKC including delta (PKC-δ), epsilon (PKC-ɛ) and theta (PKC-θ), but not eta (PKC-η), were endogenously expressed. Taken together, these results suggest that curcumin selectively inhibits IBavia a novel PKC-θ-dependent pathway, which could contribute to its neuroprotective effects in rat hippocampal neurons.
authors.affiliation: Department of Neurology, Shanghai Pudong New Area Zhoupu Hospital, Shanghai 201138, PR China.
authors.forename: Kangyong
authors.initials: K
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Gui
authors.forename: Yinyi
authors.initials: Y
authors.lastname: Sun
authors.forename: Nan
authors.initials: N
authors.lastname: Shi
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Gu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D003474:Curcumin / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology*; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D009281:Naphthalenes; C061465:calphostin complex; C489591:Prkcq protein, rat; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D003474:Curcumin; C070515:bisindolylmaleimide I