Nicotinic acetylcholine receptors regulate type 1 inositol 1,4,5-trisphosphate receptor expression via calmodulin kinase IV activation

J Neurosci Res. 2015 Apr;93(4):660-5. doi: 10.1002/jnr.23518. Epub 2014 Nov 27.

Abstract

Type 1 inositol 1,4,5-trisphosphate receptors (IP3 R-1) are among the important calcium channels regulating intracellular Ca(2+) concentration in the central nervous system. In a previous study, we showed that drugs of abuse, such as cocaine, methamphetamine, and ethanol, induced IP3 R-1 upregulation via the calcium signal transduction pathway in psychological dependence. Although nicotine, a major component in tobacco smoke, participates in psychological and/or physical dependence, it has not yet been clarified how nicotine alters IP3 R-1 expression. The present study, therefore, seeks to clarify the mechanism bgy which nicotine modifies IP3 R-1 expression by using mouse cerebral cortical neurons in primary culture. Nicotine induced dose- and time-dependent upregulation of IP3 R-1 protein following its mRNA increase, and the latter was significantly suppressed by a nonselective nicotinic acetylcholine receptors (nAChR) antagonist, mecamylamine. Both cFos and phosphorylated-cJun (p-cJun) were immediately increased in the nucleus, together with an increase of calmodulin kinase (CaMK) IV but not CaMKII expression after nicotine exposure. A nonselective inhibitor of CaMKs, KN-93, and a calcium chelating regent, BAPTA-AM, completely suppressed the expression of cFos and p-cJun in the nucleus as well as the nicotine-induced IP3 R-1 upregulation. These results indicate that nAChR activation by nicotine upregulates IP3 R-1 via increase of activator protein-1, which is a cFos and cJun dimmer, in the nucleus, with activation of Ca(2+) signaling transduction processes.

Keywords: AP-1; calcium; nicotinic acetylcholine receptors; type 1 inositol 1,4,5-trisphosphate receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzylamines / pharmacology
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Nicotinic / genetics
  • Receptors, Nicotinic / metabolism*
  • Sulfonamides / pharmacology
  • Time Factors
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*

Substances

  • Benzylamines
  • Chelating Agents
  • Inositol 1,4,5-Trisphosphate Receptors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Receptors, Nicotinic
  • Sulfonamides
  • KN 93
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Calcium