Reduced G_s protein function and Gα_s levels in leukocytes of patients with Parkinson's disease

Abstract

Early events in signal information transduction beyond dopamine, beta-adrenergic, and muscarinic receptors, involving receptor-coupled G-protein function and G alpha subunit immunoreactive levels were measured in mononuclear leukocytes (MNLs) of 12 never-treated patients with Parkinson's disease in comparison with 10 age- and sex-matched healthy control subjects. Both beta-adrenergic and dopamine receptor-coupled Gs protein function as measured by cholera toxin-sensitive, isoproterenol- and dopamine-induced increases in Gpp(NH)p-binding capacity, in MNLs of patients with Parkinson's disease were found to be significantly reduced in comparison with those in the control group. Muscarinic receptor-coupled non-Gs (Gi or G(o)) protein function: pertussis toxin-sensitive, carbamylcholine-induced increase in Gpp(NH)p-binding capacity, was not found to be significantly different between patients with Parkinson's disease and control subjects. G protein alpha subunits were measured through immunoblotting analyses with specific polyclonal antibodies against G alpha s, G alpha i, and G alpha q subunits. MNL levels of the 45-kDa species of G alpha s were found to be significantly reduced in patients with Parkinson's disease in comparison with control subjects. Other non-Gs proteins (Gi, Gq) did not show any significant quantitative differences between patients with Parkinson's disease and control subjects. The reductions in G alpha s levels in MNLs of patients with Parkinson's disease may explain the beta-adrenergic and dopamine receptor-coupled Gs protein hypofunction detected in MNLs of these patients. As previous studies have failed to observe significant changes in receptor levels in MNLs of patients with Parkinson's disease, our findings of reduced dopaminergic and beta-adrenergic receptor-coupled Gs function and of G alpha s immunoreactive levels in MNLs of Parkinson's patients point to alterations distal to these receptors at the level of the signal-transducing Gs protein.

mRNA and Protein Expression of Selective Alpha Subunits of G Proteins are Abnormal in Prefrontal Cortex of Suicide Victims

“…Because of the critical role of G proteins in signaling systems, studies in recent years have focused on their involvement in the pathophysiology of mental disorders, including affective disorders (Ozawa et al 1993;Garcia-Sevilla et al 1997, Young et al 1993Manji et al 1995;Friedman and Wang 1996;Vawter et al 2000), panic disorder (Stein et al 1995;Gurguis et al 1999a,b), Parkinson's disease (Avissar et al 1997), schizophrenia (Jope et al 1998), alcoholism (Hoffman and Tabakoff 1990;Jope et al 1998), and also in the mechanisms of action of psychoactive drugs (reviewed by Manji 1992;Dwivedi and Pandey 1997). The role of G proteins in suicidal behavior, however, has not been evaluated in greater detail.…”