Regulation of G protein receptor coupling, mood disorders and mechanism of action of antidepressants

Mood disorders are highly prevalent. Antidepressants and mood stabilizers were discovered in the 1950s, but the pathophysiology of these disorders remains undeciphered. The pharmacological bridge approach led to the construction of the catecholamine and indoleamine hypotheses for mood disorders. Biochemical research in mood disorders has lately focused on information transduction and regulatory mechanisms involving the coupling of receptors with signal transducers. G protein receptor-coupled signal transduction is regulated at various points: A proximal point is receptor coupling with G protein, regulated by G protein-coupled receptor kinases (GRKs) and β-arrestins Cytosolic regulators of G protein function are phosducin-like proteins A distal point is GTPase activity, regulated by regulators of G protein signaling (RGS). This chapter presents findings concerning the importance of these regulatory processes for the pathophysiology of mood disorders and for the mechanism of action of antidepressants. The strengths and limitations of the pharmacological bridge approach governing pathophysiological studies of mental disorders are highlighted and the possibility of future biochemical diagnostic and treatment-monitoring systems for mood disorders is addressed. Such an achievement is expected to be revolutionary, with a magnitude similar to the impact of the discovery of psychopharmacological treatments for mental disorders more than 50 years ago.