Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms

Neuropharmacology. 2016 Feb;101:439-48. doi: 10.1016/j.neuropharm.2015.10.017. Epub 2015 Oct 22.


Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca(2+) changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2::luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12-24 h in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca(2+) less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs.

Controls: We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms.

Keywords: Bipolar disorder; Calcium; Cells; Circadian rhythms; Gene; Lithium.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Animals
  • Bipolar Disorder / genetics
  • Bipolar Disorder / pathology
  • Boron Compounds / pharmacology
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism
  • Calcium Channels, L-Type / genetics*
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling / drug effects*
  • Cells, Cultured
  • Circadian Rhythm / drug effects*
  • Circadian Rhythm / genetics*
  • Female
  • Fibroblasts
  • Humans
  • Lithium / pharmacology
  • Lithium / therapeutic use*
  • Male
  • Mice
  • Middle Aged
  • NIH 3T3 Cells
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Verapamil / pharmacology
  • Young Adult


  • Boron Compounds
  • CACNA1A protein, human
  • CACNA1D protein, human
  • Calcium Channel Blockers
  • Calcium Channels
  • Calcium Channels, L-Type
  • PER2 protein, human
  • Period Circadian Proteins
  • RNA, Small Interfering
  • Lithium
  • Verapamil
  • 2-aminoethoxydiphenyl borate
  • CLOCK Proteins