RGS proteins: impact on the treatment of depression and anxiety.

Regulators of G protein signalling (RGS) proteins were first found to limit heterotrimer G protein signalling by accelerating the hydrolysis of GTP-bound to Ga subunits, thereby terminating receptor pathway signalling. Subsequently, RGS proteins have been found to act as scaffolding proteins, to interact directly and selectively to G protein-coupled receptors (GPCRs) and to act as effector modulators (Ghavami et al. 2004; McCoy & Hepler, 2009). Through all of these interactions, RGS proteins act to negatively regulate signalling pathways. The selective interactions that occur among GPCRs, G proteins and RGS proteins provide an opportunity for more selective drug targeting to a specific complex of these proteins, (McCoy & Hepler, 2009 ; Shankaranarayanan et al. 2008) rather than the traditional approach of targeting GPCRs or more recent proposals for targeting RGS proteins. Targeting select GPCR/G protein/RGS complexes may prove useful for improving the treatment of depression. Although major depression is a common disorder, treatment approaches for depression are woefully inadequate (Insel & Wang, 2009). Approximately one in six people in the USA suffer from major depressive disorder and individuals have a 16.2% lifetime prevalence for depression (Kessler et al. 2003). There are several classes of medications which are useful in the treatment of depression including selective serotonin reuptake inhibitors (SSRIs) and mixed norepinephrine/serotonin reuptake inhibitors. In fact, from recently published data on the top prescription drugs of 2010, two of these reuptake inhibitor antidepressants, escitalopram and duloxetine (Lindsley, 2011) are in the top 20 in sales in the USA. Despite the widespread use of antidepressant medications and especially reuptake inhibitors, there is a pressing need for better treatments for depression (Insel & Wang, 2009). The results from a major, large-scale clinical study, the Sequenced Treatment Alternatives to Relieve Depression trial emphasize three major problems with current antidepressant therapy. First, the current medications do not alleviate depression for a large percentage of patients. Second, when patients do respond to the medications, it takes weeks of therapy not hours or days as with most medications. Third, patients may respond to one antidepressant medication or combination of medications but not others and currently there are not methods to predict which medication or combination of medications will be effective for any individual (Insel & Wang, 2009 ; Kessler et al. 2003). It is therefore essential to identify new targets and new therapeutic approaches for the treatment of depression. The paper ‘Relationship between Rgs2 gene expression levels and anxiety and depression-like behaviour in a mutant mouse model : serotonergic involvement’ by Lifschytz et al. (2011) brings to our attention the importance of RGS protein modulation of receptor signalling in anxiety and depression. In their study, mice carrying a mutation in the RGS2 gene causing reduced expression levels were examined in several tests for anxiety and depressive–like behaviours. Mice homozygous for the RGS2 mutation demonstrated increased depressive-like behaviour while both heterozygotes and homozygotes displayed increased anxiety-like behaviours and reduced sociability. Linking their results to serotonin (5-HT)1A receptor signalling was accomplished by demonstrating that the RGS2 mutant mice have reduced hypothermic responses to the 5-HT1A/7 receptor agonist, 8-hydroxy-2-dipropylaminotetralin (DPAT). The reduced hypothermic responses suggest that RGS2 is an important modulator of 5-HT1A autoreceptor function in the raphe nucleus (Richardson-Jones et al. Address for correspondence : Dr N. A. Muma, Department of Pharmacology and Toxicology, University of Kansas, School of Pharmacy, 1251 Wescoe Hall Dr, 5064 Malott Hall, Lawrence, KS 66045, USA. Tel. : 785-864-4001 Fax : 785-864-5219 Email : [email protected]