Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium
Christina Schlecker, … , Klara Szigeti-Buck, Barbara E. Ehrlich
Christina Schlecker, … , Klara Szigeti-Buck, Barbara E. Ehrlich
Published June 1, 2006
Citation Information: J Clin Invest. 2006;116(6):1668-1674. https://doi.org/10.1172/JCI22466.
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Research Article Neuroscience

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

Abstract

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.

Authors

Christina Schlecker, Wolfgang Boehmerle, Andreas Jeromin, Brenda DeGray, Anurag Varshney, Yogendra Sharma, Klara Szigeti-Buck, Barbara E. Ehrlich

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Figure 3

Effect of NCS-1 and the E120Q mutant of NCS-1 on the activity of InsP3 R1.

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Effect of NCS-1 and the E120Q mutant of NCS-1 on the ...
(A) Single-channel recordings of InsP3R1 where downward deflections are channel openings. The top pair of traces on the left were recorded after addition of 300 nM free calcium and 2 μM InsP3, and the bottom left pair of traces show activity after addition of 2 μg/ml NCS-1 in the presence of 2 μM InsP3. In each case, the uppermost trace represents 10 seconds of continuous recording, and the bottom trace shows a 10-fold expansion of the time scale. On the right, the top pair of traces were recorded in the presence of 2 μg/ml NCS-1 in the absence of InsP3, and the bottom pair of traces were recorded after addition of 2 μg/ml E120Q, a mutant of NCS-1, in the presence of 2 μM InsP3. Averaged values from at least 3 experiments for mean open time (B) and for Po (C) of InsP3R1 corresponding to the traces shown in A. Note that NCS-1 alone did not activate InsP3R1. (D) Addition of NCS-1 (2 μg/ml) had no effect on the activity of the RyR2 activated by 300 μM calcium.