Response to lithium of a cell surface ECTO-NOX protein with time-keeping characteristics

Lithium has been used widely both as a clinical agent to treat manic depressive disorders and as a substance targeted to the regulation of the circadian cycle. In this study, we show that lithium at physiological concentrations of less than 1 μM uniquely induces an ECTO-NOX activity previously inactive from plant (soybean), murine (3T3 cells) and human (HUVEC and HeLa cells) sources and resets the period of the constitutive CNOX. The average period length of the new oscillation set induced by the presence of lithium of 23.5 min was slightly less than the period length in the absence of lithium (24 min). The constitutive period was retained in the presence of lithium but the period length was increased on an average by 4% to about 25 min. Targeting circadian rhythm abnormalities may be a particularly useful strategy in management of bipolar disorder and related illnesses since circadian cycles appear to be an inherent function conserved through evolution in all organisms and consistently implicated in the pathophysiology of bipolar disorder.