Signaling networks in the pathophysiology and treatment of mood disorders
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.
References (129)
- et al.
Molecular and cellular mechanisms of cardiac arrhythmias
Cell
(2001) Basic concepts in the study of diseases with complex genetics
Biol Psychiatry
(1999)- et al.
Enhanced protein kinase C activity and translocation in bipolar affective disorder brains
Biol Psychiatry
(1996) - et al.
Hyperfunctional G proteins in mononuclear leukocytes of patients with mania
Biol Psychiatry
(1991) - et al.
Guanine nucleotide binding proteins in opioid-dependent patients
Biol Psychiatry
(1997) - et al.
Density of guanine nucleotide-binding proteins in platelets of patients with major depression: increased abundance of the G alpha i2 subunit and down-regulation by antidepressant drug treatment
Biol Psychiatry
(1997) - et al.
Signal-transducing G proteins and antidepressant drugs: evidence for modulation of alpha subunit gene expression in rat brain
Biol Psychiatry
(1992) - et al.
Beta-adrenoceptor and post-receptor components show different rates of desensitization to desipramine
Eur J Pharmacol
(1990) - et al.
Post-receptor-mediated increases in adenylate cyclase activity after chronic antidepressant treatment: relationship to receptor desensitization
Eur J Pharmacol
(1989) - et al.
Lack of effect of chronic antidepressant treatment on Gs and Gi alpha-subunit protein and mRNA levels in the rat cerebral cortex
Neuropsychopharmacology
(1996)