Is the Na(+)-K(+)-ATPase the link between phosphoinositide metabolism and bipolar disorder?

Recent experimental work suggests involvement of the phosphatidyl inositol second messenger system in the biochemical mechanism of lithium action, but this work has not shed light on the pathophysiology of bipolar illness. Earlier work had established reduction in sodium-potassium-activated adenosine triphosphatase (Na(+)-K(+)-ATPase) activity as a consistent marker of mood in bipolar illness but had only partially illuminated mechanisms of the action of lithium. Now, advances from research in diabetic neuropathy suggest that inositol phosphate and diacylglycerol metabolism are indeed linked to Na(+)-K(+)-ATPase activity. The data are compatible with a model in which a primary decrease in Na(+)-K(+)-ATPase activity in bipolar patients can stimulate an increase in phosphoinositide hydrolysis, thereby generating the equivalent of a second messenger signal in the absence of a first message. Lithium appears to act by blocking this false second message.