Are disturbances in lipid-protein interactions by phospholipase-A 2 a predisposing factor in affective illness?

Abstract

Current theories of affective disorders do not account for many of the biological markers replicated in patient studies. We link many biological findings in a reasonable physiological relationship, compatible with mechanisms of action of pharmacological and electroshock therapies for depression. We propose that excessive phospholipase-A 2 (PLA 2) activity disrupts membrane fluidity, composition, and therefore, the activity, of membranedependent proteins. Similar disruptions in these proteins are documented in depressed patients and can be accounted for by excessive PLA 2 activity. This paradigm accounts for disturbances in the activity of Na-K-ATPase, beta 2- and alpha 2-adrenergic receptors, MAO, norepinephrine and serotonin uptake, and imipramine binding. Disturbances in other membrane-dependent proteins, tyrosine and tryptophan hydroxylase, can explain the biogenic amine hypothesis. Inhibition of glucocorticoid receptor and TRH receptor binding to their respective ligands by PLA 2 may explain patient nonsuppression in the Dexamethasone Suppression Test and poor response in the TRH stimulation test. Physiological regulators of PLA 2 activity; calcium, cortisol, estrogen, progesterone, andPGE 2 are documented abnormalities in some patients with affective disorders and consistent with excessive PLA 2 activity. Thus, postpartum depression and premenstrual tension syndrome may be described in the paradigm. The mechanisms of action of tricyclic antidepressants, lithium, electroconvulsive shock, and some novel antimanic agents can be described in terms of alterations of PLA 2 activity. Interestingly, ethanol perturbs membrane fluidity and membrane-bound enzymes in a manner similar to excessive PLA 2 activity. A hereditary factor predisposing patients to affective disorders may be a gene defect at either PLA 2 or in its regulation.