Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium.
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.
Schlecker
Christina
C
Department of Pharmacology, Yale University, New Haven, Connecticut 06520-8066, USA.
Boehmerle
Wolfgang
W
Jeromin
Andreas
A
DeGray
Brenda
B
Varshney
Anurag
A
Sharma
Yogendra
Y
Szigeti-Buck
Klara
K
Ehrlich
Barbara E
BE
D000818:Animals; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D006801:Humans; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008094:Lithium / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D051580:Neuronal Calcium-Sensor Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; C101464:frequenin calcium sensor proteins; D008094:Lithium; D002118:Calcium