Signaling networks in the pathophysiology and treatment of mood disorders

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Abstract

Over the past decade, the focus of research into the pathophysiology of mood disorders (bipolar disorder and unipolar depression in particular) has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Second messenger systems rely on cell membrane receptors to relay information from the extracellular environment to the interior of the cell. Within the cell, this information is processed and altered, eventually to the point where gene and protein expression patterns are changed. There is a preponderance of evidence implicating second messenger systems and their primary contact with the extracellular environment, G proteins, in the pathophysiology of mood disorders. After an introduction to G proteins and second messenger pathways, this review focuses on the evidence implicating G proteins and two second messenger systems—the adenylate cyclase (cyclic adenosine monophosphate, cAMP) and phosphoinositide (protein kinase C, PKC) intracellular signaling cascades—in the pathophysiology and treatment of bipolar disorder and unipolar depression. Emerging evidence implicates changes in cellular resiliency, neuroplasticity and additional cellular pathways in the pathophysiology of mood disorders. The systems discussed within this review have been implicated in neuroplastic processes and in modulation of many other cellular pathways, making them likely candidates for mediators of these findings.

Section snippets

Basic science

G proteins (GTP-binding proteins) transduce a signal from a seven transmembrane G protein-coupled receptor to intracellular second messengers (Fig. 1). By definition, G proteins have the intrinsic ability to bind guanosine triphosphate (GTP), a common molecule in the cytoplasm of cells. Four main categories, comprising many members, of G proteins exist: Gs, Gi, Gq and G12. Gs stimulates the enzyme adenylate cyclase and regulates calcium and potassium channels, Gi inhibits the actions of

Basic science

The G protein-linked signal transduction pathway involving the enzyme adenylate cyclase (also referred to as adenylyl cyclase) is well characterized (Fig. 2) [51]. Adenylate cyclase, of which there are several distinct forms, is an enzyme that converts ATP to the second messenger, cyclic cAMP. Depending on the particular G protein-coupled receptor and linked G protein, cAMP is either up or downregulated. As mentioned previously, Gs is involved in stimulating adenylate cyclase whereas Gi

Basic science

A second well-characterized G protein-linked signal transduction pathway involves the breakdown of a cell membrane component, phosphoinositide 4,5-bisphosphate (PIP2) (Fig. 3) [89]. This pathway is also referred to as the phophotidylinositol (PI) pathway. PI is coupled to muscarinic M1, M2, M3, noradrenergic α1 and seronergic 5HT2 receptors via the Gq α subunit. Following binding of a ligand to its extracellular receptor, GTP binding induces hydrolysis of PIP2 to form diacylglycerol (DAG) and

Concluding remarks

Results implicating abnormalities in second messenger pathways can be difficult to interpret based on significant overlap between pathways and a combination of feedforward and feedback control (see Fig. 4 for a synopsis of findings). For example, while the transcription factor CREB is best known as a protein that can be phosphorylated by PKA, there is evidence that both PKC and CaM-Ks phophorylate CREB at the same site as PKA, modulating its activity as a transcription factor in the same manner

Acknowledgements

We would like to acknowledge the support of the National Institute of Mental Health and the Theodore and Vada Stanley Foundation.

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