Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders

Abstract

The molecular medicine revolution has resulted in a more complete understanding about the etiology and pathophysiology of a variety of illnesses. This remarkable progress reflects in large part the elucidation of the basic mechanisms of signal transduction, and the application of the powerful tools of molecular biology to the study of human disease. Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated signal transduction pathways, in particular the stimulatory guanine nucleotide binding protein (Gs)/cyclic AMP and protein kinase C pathways, in the pathophysiology and treatment of mood disorders. Recent studies have also shown that mood stabilizers exert neurotrophic and neuroprotective effects not only in preclinical paradigms, but also in humans. Together, these studies suggest that mood disorders may be associated with impaired neuroplasticity and cellular resiliency, findings that may have major implications for our understanding of mood disorders, and for the development of improved therapeutics.

Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of Mania

“…Furthermore, chronic lithium treatment has been shown to dramatically reduce the hippocampal levels of the protein MARCKS, which is one of the PKC substrates implicated in regulating long-term neuroplastic events (Lenox et al, 1992). Notably, the anti-manic agent VPA, which is structurally dissimilar to lithium, produces very similar effects to those of lithium on PKC α and ε isozymes and on MARCKS, one of the PKC substrates (Chen et al, 1994; Lenox and Hahn, 2000; Manji and Chen, 2000; Manji and Lenox, 1999, 2000; Watson et al, 1998). …”

“…Binding of neurogranin to CaM can be restored by dephosphorylation of neurogranin with protein phosphatase I (PP1), protein phosphotase 2A (PP2A), and by the calcium-CaM dependent protein phosphatase 2B (Li et al, 2003). It is not only a major PKC target, but also an upstream regulator of three major signalling cascades—calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), and PKC—that are thought to play important roles in the pathophysiology and treatment of severe mood disorders (Barbiero et al, 2007; Coyle and Duman, 2003; Manji and Chen, 2000; Popoli et al, 2001). Under manic conditions, increased phosphorylation of neurogranin by PKC (Figure 3) liberates calmodulin towards activation of CAMKII and CAMKIV, which is the key for the formation of LTP.…”

Lateralized Caudate Metabolic Abnormalities in Adolescent Major Depressive Disorder: A Proton MR Spectroscopy Study

“…Phosphocholine, a major choline signal contributor and a metabolite of phosphatidylcholine, is an important source of diacylglycerol, the second messenger known to participate in intracellular signal transduction pathways (29,37,38) hypothesized to contribute to the pathogenesis of major depression (39).…”

Divalproex Sodium vs Placebo for the Treatment of Irritability in Children and Adolescents with Autism Spectrum Disorders

“…These two mechanisms are of specific interest in ASD given theories of decreased inhibitory control in autism (Casanova et al, 2003), high frequency of seizures and epileptiform EEGs in this population, especially in individuals with lower IQs (Amiet et al, 2008) and the increasing evidence to support a role of gene expression abnormalities in the pathophysiology of multiple neuropsychiatric disorders (Szyf M et al, 2009). Other mechanisms that may or may not be relevant to the treatment of irritability include functional blockade of voltage-sensitive sodium channels, attenuation of NMDA mediated excitation, influences on serotonin and norepinephrine function, effects on second messenger systems, and potentially neuroprotective effects (Manji and Chen, 2000, Yasuda et al , 2009,Chen et al 1999). …”