Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

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Abstract
Abnormalities in the density of neuroreceptors that regulate norepinephrine and serotonin release have been repeatedly reported in brains of suicide victims with mood disorders. Recently, the modulation of the [35S]GTPγS binding to G-proteins has been introduced as a suitable measure of receptor activity in postmortem human brain. The present study sought to evaluate the function of several G-protein coupled receptors in postmortem brain of suicide victims with mood disorders. Concentration-response curves of the [35S]GTPγS binding stimulation by selective agonists of α2-adrenoceptors, 5-HT1A serotonin, μ-opioid, GABAB, and cholinergic muscarinic receptors were performed in frontal cortical membranes from 28 suicide victims with major depression or bipolar disorder and 28 subjects who were matched for gender, age and postmortem delay. The receptor-independent [35S]GTPγS binding stimulation by mastoparan and the G-protein density were also examined. The α2A-adrenoceptor-mediated stimulation of [35S]GTPγS binding with the agonist UK14304 displayed a 4.6-fold greater sensitivity in suicide victims than in controls, without changes in the maximal stimulation. No significant differences were found in parameters of 5-HT1A serotonin receptor and other receptor-mediated [35S]GTPγS binding stimulations. The receptor-independent activation of G-proteins was similar in both groups. Immunoreactive densities of Gαi1/2-, Gαi3-, Gαo-, and Gαs-proteins did not differ between suicide victims and controls. In conclusion, α2A-adrenoceptor sensitivity is increased in the frontal cortex of suicide victims with mood disorders. This receptor supersensitivity is not related to an increased amount or enhanced intrinsic activity of G-proteins. The new finding provides functional support to the involvement of α2-adrenoceptors in the pathogenesis of mood disorders.