The involvement of guanine nucleotide binding proteins in the pathogenesis and treatment of affective disorders

Abstract

Guanine nucleotide binding (G) proteins play a pivotal role in postreceptor information transduction. An important characteristic of G proteins is their increased guanine nucleotide binding following agonist stimulation, which in turn leads to their activation. We have developed a method that enables the measurement of early events in signal transduction beyond receptors, through activated receptor-coupled guanine nucleotide exchange on G proteins. Using this method, lithium was recently demonstrated to inhibit the coupling of both muscarinic cholinergic and β-adrenergic receptors to pcrtussis toxin-sensitive and cholera toxin-sensitive G proteins, respectively, thus suggesting alteration of the function of G protein by lithium, as the single site for both the antimanic and antidepressant effects of this drug. One of the most puzzling aspects of the ability of lithium to ameliorate the manic-depressive condition is its relatively selective action upon the central nervous system (CNS). It was previously shown that lithium selectively attenuated the function of G s proteins in the CNS. In the present study, we show that inhibition by lithium of muscarinic receptor-coupled G protein function is also selective to the CNS. The clinical profile of lithium, carbamzepine, and electroconvulsive treatment ( (ECT), agents that are effective in the prevention and treatment of bipolar affective disorder, differs from that of purely antidepressant drugs. Antidepressant drugs are effective in the acute treatment and prevention of depression only, and can even precipitate hypomanic or manic “switches”, or “rapid cycling” between mania and depression. We have investigated and compared the effects of chronic antibipolar and antidepressant treatments on receptor-coupled G protein function. Antibipolar treatments (lithium, carbamazepine, ECT) attenuate both receptor-coupled G s and non-G s (i.e., G i, G o) proteins function; in contrast, only G s protein function is inhibited by antidepressant drugs [either tricyclics or monoamine oxidase (MAO) inhibitors]. Moreover, an integral adrenergic neuronal system is required for antidepressant inhibition of G s protein function, as pretreatment with the noradrenergic neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) specifically abolishes the effects of antidepressant drugs on G s protein, whereas antibipolar drug effects on G protein function are unaffected by DSP-4. Our results suggest that attenuation of β-adrenergic receptor-coupled G s protein function, which is common to both antidepressant and antibipolar treatments, may be the mechanism underlying their antidepressant therapeutic efficacy. Muscarinic receptor-coupled, pertussis toxin-sensitive G proteins (i.e., G i, G o) may be the molecular site for the antimanic therapeutic effects of antibipolar treatments. The ability to measure early events in signal transduction using the technique of receptor-coupled guanine nucleotide exchange on G proteins enabled us to extend our studies to examine whether altered G protein function is of pathophysiological importance in bipolar affective disorder. The coupling of both muscarinic and β-adrenergic receptors to pertussis toxin- or cholera toxin-sensitive G proteins was compared among untreated manic patients, lithium-treated euthymic bipolar patients, and healthy volunteers using mononuclear leukocyte membrane preparations. Hyperactive function of G proteins is detected in untreated manic patients. On the other hand, lithium-treated euthymic bipolar patients show G protein responses to agonist activation no different from the healthy volunteers. G protein-regulated adenylate cyclase and phosphatidylinositol second messenger systems are highly inter-regulated and cross-regulated. By mathematically analyzing the dynamical properties of these systems, it is proposed that hyperfunction of G proteins, either as a trait marker or as a state function, leads to an unstable “catastrophic” dynamic system, characteristic of a manic or a depressed state, and that lithium treatment attenuates G protein function ad dampens the oscillatory system to yield a stable state. This mathematical model thus encompasses the available knowledge on the perturbation of G proteins function by antibipolar and antidepressant treatments, as well as the findings on hyperfunctional G proteins in bipolar affective patients, and addresses the oscillatory occurrence of symptoms characteristic of manic-depressive illness; the ability of lithium and other antibipolar treatments to ameliorate both poles of the disorder; and “manic switch” and “rapid cycling” dynamic side effects of antidepressant drugs.