title: Methamphetamine acutely inhibits voltage-gated calcium channels but chronically up-regulates L-type channels.
abstract: In neurons, calcium (Ca(2+) ) channels regulate a wide variety of functions ranging from synaptic transmission to gene expression. They also induce neuroplastic changes that alter gene expression following psychostimulant administration. Ca(2+) channel blockers have been considered as potential therapeutic agents for the treatment of methamphetamine (METH) dependence because of their ability to reduce drug craving among METH users. Here, we studied the effects of METH exposure on voltage-gated Ca(2+) channels using SH-SY5Y cells as a model of dopaminergic neurons. We found that METH has different short- and long-term effects. A short-term effect involves immediate (< 5 min) direct inhibition of Ca(2+) ion movements through Ca(2+) channels. Longer exposure to METH (20 min or 48 h) selectively up-regulates the expression of only the CACNA1C gene, thus increasing the number of L-type Ca(2+) channels. This up-regulation of CACNA1C is associated with the expression of the cAMP-responsive element-binding protein (CREB), a known regulator of CACNA1C gene expression, and the MYC gene, which encodes a transcription factor that putatively binds to a site proximal to the CACNA1C gene transcription initiation site. The short-term inhibition of Ca(2+) ion movement and later, the up-regulation of Ca(2+) channel gene expression together suggest the operation of cAMP-responsive element-binding protein- and C-MYC-mediated mechanisms to compensate for Ca(2+) channel inhibition by METH. Increased Ca(2+) current density and subsequent increased intracellular Ca(2+) may contribute to the neurodegeneration accompanying chronic METH abuse. Methamphetamine (METH) exposure has both short- and long-term effects. Acutely, methamphetamine directly inhibits voltage-gated calcium channels. Chronically, neurons compensate by up-regulating the L-type Ca(2+) channel gene, CACNA1C. This compensatory mechanism is mediated by transcription factors C-MYC and CREB, in which CREB is linked to the dopamine D1 receptor signaling pathway. These findings suggest Ca(2+) -mediated neurotoxicity owing to over-expression of calcium channels.
authors: Bekesy Laboratory of Neurobiology, Pacific Biosciences Research Center, University of Hawaii, Honolulu, Hawaii, USA.
authors: Marilou A
authors: MA
authors: Andres
authors: Bekesy Laboratory of Neurobiology, Pacific Biosciences Research Center, University of Hawaii, Honolulu, Hawaii, USA.|Department of Biology, University of Hawaii, Honolulu, Hawaii, USA.
authors: Ian M
authors: IM
authors: Cooke
authors: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors: Frederick P
authors: FP
authors: Bellinger
authors: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors: Marla J
authors: MJ
authors: Berry
authors: Bekesy Laboratory of Neurobiology, Pacific Biosciences Research Center, University of Hawaii, Honolulu, Hawaii, USA.
authors: Maribel M
authors: MM
authors: Zaporteza
authors: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors: Rachel H
authors: RH
authors: Rueli
authors: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors: Stephanie M
authors: SM
authors: Barayuga
authors: Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
authors: Linda
authors: L
authors: Chang
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D006801:Humans; D008694:Methamphetamine / Q000494:pharmacology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology*
chemical_list: C079146:CACNA1C protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D008694:Methamphetamine
keywords: CACNA1B; CACNA1C; CREB; MYC; calcium channel; calcium signaling; methamphetamine