Lithium sensitive G protein hyperfunction: a dynamic model for the pathogenesis of bipolar affective disorder.

Abstract

Guanine nucleotide binding proteins (G proteins) play a pivotal role in information transduction from various membrane receptors to a variety of intracellular effector systems. By influencing the metabolism of adenylate cyclase and phosphatidylinositol, G proteins affect the activities of both cAMP-dependent protein kinase (kinase A) and protein kinase C. The hypothesis of this present study addresses the oscillatory behavior of symptoms observed in manic-depressive patients by suggesting that the cellular phosphorylation state in the central nervous system, which results from the relative activity of protein kinase A and protein kinase C, determines the affective state. From this hypothesis, we developed a kinetic model based on self- and inter-regulatory steps between these two protein kinase systems. The solutions of the differential equations governing this kinetic model can describe oscillatory pathological affective states. More specifically, we show that hyperfunction of G proteins leads to an unstable 'catastrophic' dynamic system characteristic of a manic or depressive state, and that lithium treatment attenuates G protein function and damps the oscillatory system to yield a stable state.