CaMKIIα interacts with M4 muscarinic receptors to control receptor and psychomotor function

Ming Lei Guo, Eugene E. Fibuch, Xian Yu Liu, Eun Sang Choe, Shilpa Buch, Li Min Mao, John Q. Wang

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the mammalian brain and are essential for neuronal functions. These receptors are believed to be actively regulated by intracellular signals, although the underlying mechanisms are largely unknown. In this study, we show that Ca 2+/calmodulin-dependent protein kinase II (CaMKII) binds directly and selectively to one of five mAChR subtypes, M4 receptors (M4Rs), at their C-terminal regions of second intracellular loops. This binding relies on Ca 2+ activation of the kinase and leads to the phosphorylation of M4Rs at a specific threonine site (Thr145). Complementary in vivo studies in rat striatal neurons enriched with M4Rs confirm that rising Ca2+ recruits CaMKIIα to M4Rs to potentiate receptor signalling, which controls behavioural sensitivity to dopamine stimulation in an activity-dependent manner. Our data identify a new model of protein-protein interactions. In a Ca 2+-sensitive manner, CaMKIIα regulates M4R efficacy and controls the acetylcholine-dopamine balance in the basal ganglia and also the dynamics of movement.

Original languageEnglish (US)
Pages (from-to)2070-2081
Number of pages12
JournalEMBO Journal
Volume29
Issue number12
DOIs
StatePublished - Jun 16 2010

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Keywords

  • Calcium
  • Cocaine
  • Phosphorylation
  • Striatum
  • cAMP

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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