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Ryanodine receptor‐2 upregulation and nicotine‐mediated plasticity
Author(s) -
Ziviani Elena,
Lippi Giordano,
Bano Daniele,
Munarriz Eliana,
Guiducci Stefania,
Zoli Michele,
Young Kenneth W,
Nicotera Pierluigi
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.279
Subject(s) - ryanodine receptor , downregulation and upregulation , creb , nicotine , biology , endoplasmic reticulum , microbiology and biotechnology , sigma 1 receptor , neuroscience , endocrinology , pharmacology , receptor , agonist , transcription factor , biochemistry , gene
Nicotine, the major psychoactive component of cigarette smoke, modulates neuronal activity to produce Ca 2+ ‐dependent changes in gene transcription. However, the downstream targets that underlie the long‐term effects of nicotine on neuronal function, and hence behaviour, remain to be elucidated. Here, we demonstrate that nicotine administration to mice upregulates levels of the type 2 ryanodine receptor (RyR2), a Ca 2+ ‐release channel present on the endoplasmic reticulum, in a number of brain areas associated with cognition and addiction, notably the cortex and ventral midbrain. Nicotine‐mediated RyR2 upregulation was driven by CREB, and caused a long‐lasting reinforcement of Ca 2+ signalling via the process of Ca 2+ ‐induced Ca 2+ release. RyR2 upregulation was itself required for long‐term phosphorylation of CREB in a positive‐feedback signalling loop. We further demonstrate that inhibition of RyR‐activation in vivo abolishes sensitization to nicotine‐induced habituated locomotion, a well‐characterised model for onset of drug dependence. Our findings, therefore, indicate that gene‐dependent reprogramming of Ca 2+ signalling is involved in nicotine‐induced behavioural changes.