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Methamphetamine acutely inhibits voltage‐gated calcium channels but chronically up‐regulates L‐type channels
Author(s) -
Andres Marilou A.,
Cooke Ian M.,
Bellinger Frederick P.,
Berry Marla J.,
Zaporteza Maribel M.,
Rueli Rachel H.,
Barayuga Stephanie M.,
Chang Linda
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13104
Subject(s) - creb , voltage dependent calcium channel , meth , methamphetamine , calcium channel , gene expression , chemistry , ion channel , microbiology and biotechnology , biology , transcription factor , pharmacology , gene , calcium , biochemistry , receptor , monomer , organic chemistry , acrylate , polymer
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 ‐ SY 5Y 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 CACNA 1C gene, thus increasing the number of L‐type Ca 2+ channels. This up‐regulation of CACNA 1C is associated with the expression of the cAMP ‐responsive element‐binding protein (CREB), a known regulator of CACNA 1C gene expression, and the MYC gene, which encodes a transcription factor that putatively binds to a site proximal to the CACNA 1C 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.