Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium

J Clin Invest. 2006 Jun;116(6):1668-74. doi: 10.1172/JCI22466. Epub 2006 May 11.


Regulation and dysregulation of intracellular calcium (Ca2+) signaling via the inositol 1,4,5-trisphosphate receptor (InsP3R) has been linked to many cellular processes and pathological conditions. In the present study, addition of neuronal calcium sensor-1 (NCS-1), a high-affinity, low-capacity, calcium-binding protein, to purified InsP3R type 1 (InsP3R1) increased the channel activity in both a calcium-dependent and -independent manner. In intact cells, enhanced expression of NCS-1 resulted in increased intracellular calcium release upon stimulation of the phosphoinositide signaling pathway. To determine whether InsP3R1/NCS-1 interaction could be functionally relevant in bipolar disorders, conditions in which NCS-1 is highly expressed, we tested the effect of lithium, a salt widely used for treatment of bipolar disorders. Lithium inhibited the enhancing effect of NCS-1 on InsP3R1 function, suggesting that InsP3R1/NCS-1 interaction is an essential component of the pathomechanism of bipolar disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bipolar Disorder* / drug therapy
  • Bipolar Disorder* / metabolism
  • Bipolar Disorder* / physiopathology
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Calcium Signaling / physiology*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Electrophysiology
  • Humans
  • In Vitro Techniques
  • Inositol 1,4,5-Trisphosphate Receptors
  • Lithium* / metabolism
  • Lithium* / therapeutic use
  • Mice
  • Neuronal Calcium-Sensor Proteins
  • Neurons / cytology
  • Neurons / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • PC12 Cells
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • Calcium Channels
  • Calcium-Binding Proteins
  • ITPR1 protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • Receptors, Cytoplasmic and Nuclear
  • Ryanodine Receptor Calcium Release Channel
  • frequenin calcium sensor proteins
  • Lithium
  • Calcium