کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2493134 1556614 2016 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Calcium channel genes associated with bipolar disorder modulate lithium's amplification of circadian rhythms
ترجمه فارسی عنوان
ژنهای کانال کلسیم مرتبط با اختلال دوقطبی موجب تقویت لیتیوم ریتم های روزانه می شود
کلمات کلیدی
ریتم های دورانی، کلسیم، لیتیم، اختلال دو قطبی، ژن، سلول ها
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب رفتاری
چکیده انگلیسی


• Calcium channel antagonists attenuate the effect of lithium on circadian rhythm amplitude.
• Knockdown of calcium channel genes blocks the effect of lithium on circadian rhythm amplitude.
• CACNA1C genotype is associated with the degree of rhythm amplification by lithium.
• CACNA1C expression in fibroblasts is rhythmic in controls but less so in bipolar disorder.

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 Ca2+ 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 Ca2+ 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 101, February 2016, Pages 439–448
نویسندگان
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