Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

González-Maeso, Javier; Meana, J. Javier

doi:10.2174/157015906776359586

Cited by 29 publications

(17 citation statements)

References 160 publications

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“…Therefore, alterations in any of these players may have implications beyond α 2 ARs. Nevertheless, alterations in these key accessory proteins may help to provide a mechanistic basis for the α 2 AR dysregulation in depressive disorders in addition to potential changes in the G proteins themselves, a topic which has been well-reviewed by Gonzalez-Maeso and Meana (Gonzalez-Maeso and Meana, 2006). …”

Section: Receptor Accessory Proteins In Depressive Disordersmentioning

confidence: 99%

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

Cottingham

Wang

2012

Neuroscience & Biobehavioral Reviews

102

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Dysfunction in noradrenergic neurotransmission has long been theorized to occur in depressive disorders. The α2 adrenergic receptor (AR) family, as a group of key players in regulating the noradrenergic system, has been investigated for involvement in the neurobiology of depression and mechanisms of antidepressant therapies. However, a clear picture of the α2ARs in depressive disorders has not been established due to the existence of apparently conflicting findings in the literature. In this article, we report that a careful accounting of methodological differences within the literature can resolve the present lack of consensus on involvement of α2ARs in depression. In particular, the pharmacological properties of the radioligand (e.g. agonist versus antagonist) utilized for determining receptor density are crucial in determining study outcome. Upregulation of α2AR density detected by radiolabeled agonists but not by antagonists in patients with depressive disorders suggests a selective increase in the density of high-affinity conformational state α2ARs, which is indicative of enhanced G protein coupling to the receptor. Importantly, this high-affinity state α2AR upregulation can be normalized with antidepressant treatments. Thus, depressive disorders appear to be associated with increased α2AR sensitivity and responsiveness, which may represent a physiological basis for the putative noradrenergic dysfunction in depressive disorders. In addition, we review changes in some key α2AR accessory proteins in depressive disorders and discuss their potential contribution to α2AR dysfunction.

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Section: Receptor Accessory Proteins In Depressive Disordersmentioning

confidence: 99%

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

Cottingham

Wang

2012

Neuroscience & Biobehavioral Reviews

102

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“…Thus, in agreement with our previous discussion (see Section 2.) it is proposed that TM domains are mainly involved in less plastic arrangements of the GPCR 3D-conformation and in stable RRIs as indicated by several groups [29, 59-62]. On the other hand, the domains with a high DI are particularly suited for more dynamic interactions, such as those with allosteric modulators, but also possibly for more flexible RRIs.…”

Section: A Bioinformatics Analysis Of the A2acb1-d2 Trimeric Recepmentioning

confidence: 99%

Theoretical Considerations on the Topological Organization of Receptor Mosaics

Agnati¹,

Fuxé²,

Woods³

et al. 2009

CPPS

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The concept of Receptor Mosaic (RM) is discussed; hence the integrative functions of the assemblage of G-protein coupled receptors physically interacting in the plane of the plasma membrane. The main focus is on a heterotrimer of G-protein coupled receptors, namely the A2A-D2-CB1 receptor trimer. A bioinformatics analysis was carried out on the amino acid sequence of these receptors to indicate domains possibly involved in the receptor-receptor interactions. Such a bioinformatic analysis was also carried out on the RM formed by mGLU R5, D2 and A2A.The importance of topology, i.e., of the reciprocal localisation of the three interacting receptors in the plan of the membrane for the RM integrative functions is underlined. However, it is also pointed out that this fundamental aspect still waits techniques capable of an appropriate investigation. Finally, it is discussed how RM topology can give hints for a structural definition of the concept of hub receptor. Thus, just as in any network, the receptor operating as a hub is the one that in the molecular network formed by the receptors has the highest number of inputs.

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“…GPCRs are widely regarded as highly drugable targets, although GPCRs have not been traditional targets for anti-cancer drug development [ 44 ]. Traditional GPCR targeted drugs include those that interfere with neurotransmitter signaling, such as dopamine and serotonin receptor antagonists and are widely prescribed to treat mood disorders [ 45 ]. Recent reports suggest that many of these drugs display anti-cancer activity in pre-clinical models, including breast cancer models [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and evaluation of network modules for the prognosis of basal-like breast cancer

Hallett

Cockburn

et al. 2015

Oncotarget

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PurposeBasal-like breast cancer (BLBC) is a molecular subtype of breast cancer associated with poor clinical outcome, although some patients with BLBC experience long-term survival. Apart from nodal status, current clinical/histopathological variables show little capacity to identify BLBC patients at either high- or low-risk of disease recurrence. Accordingly, we sought to develop a network based genomic predictor for predicting the outcome of patients with BLBC.Experimental DesignWe performed network analysis on global gene expression profiling data of BLBCs, and identified BLBC network modules associated with AP-1 transcription, G-protein coupled receptors, and T-, B-, and NK-cells that are significant predictors of BLBC patient survival.ResultsIn gene expression and tissue microarray (TMA) validation cohorts of 210 and 102 BLBC patients, respectively, the identified network modules were robustly associated with patient outcome. In the gene expression validation cohort, the Kaplan-Meier estimate for 10-year survival in the low-risk group was 90%, whereas in the high-risk group it was a 56%. In the TMA cohort, the Kaplan-Meier estimate for 10-year survival in the low-risk group was 98%, whereas in the high-risk group it was 71%.ConclusionsThe capacity to distinguish between patients with BLBC at high- or low-risk of recurrence at the time of diagnosis could permit timely intervention with more aggressive therapeutic regimens in those patients predicted to be high-risk, and to avoid such therapy in low-risk patients.

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Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

Cited by 29 publications

References 160 publications

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

α2 adrenergic receptor dysregulation in depressive disorders: Implications for the neurobiology of depression and antidepressant therapy

Theoretical Considerations on the Topological Organization of Receptor Mosaics

Identification and evaluation of network modules for the prognosis of basal-like breast cancer

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