Elsevier

Psychiatry Research

Volume 112, Issue 2, 10 October 2002, Pages 111-119
Psychiatry Research

Epinephrine- and thrombin-stimulated high-affinity GTPase activity in platelet membranes from patients with psychiatric disorders

https://doi.org/10.1016/S0165-1781(02)00189-0Get rights and content

Abstract

Although heterotrimeric guanine nucleotide-binding regulatory (G) proteins have been implicated in the pathophysiology of mental illnesses (especially mood disorders), direct evidence has been scarce. This study was designed to reveal possible abnormalities of receptor-coupled G protein function in platelets in patients with psychiatric disorders such as depression and schizophrenia. The functional status of α2A-adrenergic receptor-coupled Gi2 and thrombin receptor-coupled G proteins (Gi2+Gq) was determined by the increase in high-affinity GTPase activity in response to epinephrine and thrombin, respectively, in platelet membranes from 18 patients with mood disorders (15 unipolar and three bipolar subtype), 13 schizophrenic patients, four neurotic patients and 29 healthy control subjects. Neither α2A-adrenergic receptor-coupled Gi2 nor thrombin receptor-coupled Gq was functionally altered in platelets from psychiatric patients compared with control subjects. No significant correlation was observed between these biochemical measures in platelets and severity of psychopathological symptoms. The functional coupling efficiency of G proteins with receptors appears intact, at least between α2A-adrenergic receptors and Gi2, and between thrombin receptors and Gq, in platelets from patients with psychiatric disorders.

Introduction

Although several decades have passed since classical monoamine hypotheses of depression were proposed (Schildkraut, 1965, Coppen, 1969), numerous questions remain about the primary abnormalities implicated in the pathogenesis of depressive disorders and the target sites of antidepressant treatments. In recent years, biochemical and pharmacological research on depressive disorders has focused on signal transduction mechanisms beyond membrane receptors, including guanine nucleotide-binding regulatory (G) proteins. G proteins are a structurally homologous family of heterotrimeric proteins consisting of α, β and γ subunits, which play a pivotal role in post-receptor information transduction as a crucial point of convergence in the transmission of signals from a variety of neurotransmitter receptors to a series of downstream cellular effectors, such as second messenger-generating enzymes and ion channels (Gilman, 1987, Birnbaumer et al., 1990, Hepler and Gilman, 1992). Alterations in G proteins have been thus regarded as potential pathophysiological states underlying many diseases, including mental disorders (Manji, 1992, Hudson et al., 1993, Spiegel et al., 1993).

Human blood platelets contain several receptors, G proteins and intracellular signaling cascade components, and have long been utilized as a peripheral model of receptor-mediated signal transduction mechanisms in the central nervous system. Although many studies have been reported with respect to platelet α2-adrenergic receptor levels in patients with affective disorders (for review, see Elliott, 1991), the functional activity of platelet G proteins coupled with α2-adrenergic receptors has been little studied. In platelet membranes, we previously reported on epinephrine-stimulated high-affinity GTPase activity derived from G proteins coupled to α2A-adrenergic receptors (Odagaki et al., 1993). It was also shown that thrombin stimulated the activity very effectively and that the increases elicited by these two compounds were not additive, in good accordance with a notion that thrombin receptors were coupled to phosphoinositide turnover, as well as to adenylyl cyclase inhibition, through the Gq and Gi families, respectively (Grandt et al., 1986, Houslay et al., 1986, Benka et al., 1995).

The present study was designed to explore possible abnormalities of G protein function by means of epinephrine- and thrombin-stimulated high-affinity GTPase activity in psychiatric disorders such as depression and schizophrenia compared with healthy control subjects. In addition, the biochemical measures were correlated with psychopathological rating scales to unravel potential relationships between them.

Section snippets

Subjects

All patients were diagnosed according to ICD-10 criteria and divided into three groups, i.e. mood disorders (n=18), schizophrenic disorders (n=13) and neurotic disorders (n=4). All of the mood disorder patients [10 female and eight male subjects; age 42.9±14.7 years (mean±S.D.), 22–77 years] were depressed [15 unipolar subtype (F32.- or F33.-) and two bipolar subtype (F31.3)], except for one bipolar patient with hypomanic symptoms (F31.0). The severity of depression was evaluated using the Beck

Results

Fig. 1 shows representative concentration–response curves of epinephrine- and thrombin-stimulated high-affinity GTPase activity in human platelet membranes. When compared using the same platelet membranes prepared from each subject, thrombin-stimulated increase in high-affinity GTPase activity was always higher than the response elicited by epinephrine. In our previous investigation, the increases in high-affinity GTPase activity elicited by maximally effective concentrations of epinephrine and

Discussion

Human blood platelets have frequently been used as a peripheral model of central monoamine neurons in the field of biological psychiatry. Based on monoamine receptor hypotheses for mood disorders, the signaling pathway mediated by platelet α2-adrenergic receptors has been intensively investigated as one of the most promising biological markers of depression. In fact, there is general agreement that α2-adrenergic receptor binding sites in platelets are, when measured with radiolabeled agonists,

Acknowledgements

This research was supported by Grant 09670970 from the Ministry of Education, Science and Culture of Japan. The authors thank Ms Yuki Sasaki for her technical assistance and Dr Takahiro Matsuoka (Department of Neuropsychiatry, Saitama Medical School) for his help with the statistical analysis.

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