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Agonist-dependent and -independent dopamine-1-like receptor signalling differentially regulates downstream effectors.

Significance Statement: Two sites of the same coin

How is it possible that constitutive signaling of D1-class receptors increases ion transport and energy consumption whereas dopamine is well known to decreases NHE- and Na,K-ATPase-activity via D1-class receptors? The manuscript provides the answer. Constitutive D1-class signaling permanently targets gene transcription, resulting in higher expression-levels and higher effector-protein-activity, whereas dopamine temporarily decreases effector protein function. The manuscripts opens an explanation to the dilemma that inverse-agonist and agonists can mediate similar beneficial effects, by showing that inverse agonists decrease the constitutively up-regulated gene expression. In the artificial system of over-expressing D1-class receptors, constitutive D1-class receptor signaling cannot be regulated on transcriptional level of the D1-class receptors. Adjustment of constitutive D5R-signaling on protein-level is shown to be sensitive to GRK2. Given that GRKs regulate agonist-occupied GPCRs-signaling, opens the question, which GPCR(s) is permanently stimulated by which endogenously expressed agonist(s) to regulates constitutive D5R signaling?  Dr. Dirk Roosterman likes to explore new opportunities and welcomes research positions in Europe and North America.

 

Journal Reference

Roosterman D. FEBS J. 2014 Nov;281(21):4792-804.

University Hospital Münster, Germany.

Abstract

De-regulation of energy metabolism by the dopaminergic system is linked to neurological diseases such as schizophrenia and bipolar disorder. Inverse agonists are thought to be more beneficial in treating neurological diseases than neutral antagonists, but only limited experimental data are available regarding the impact of constitutive signalling on energy metabolism. The aim of the present study was to assess the impact of constitutive dopamine-1 receptor (D1R) and dopamine-5 receptor  (D5R)  signalling  on  downstream targets in transiently and stably transfected HEK293T cells. The high constitutive activity of D5R was accompanied by increased Na(+)/H(+) exchanger (NHE) activity and accelerated glucose degradation due to increased transcription and translation of the Na, K-ATPase-{Alpha}3 and NHE-2. Chronic treatment with an agonist increased the mRNA levels of the {Alpha}2 Na,K-ATPase, NHE-2 and NHE-3. Constitutive D5R activation of a cAMP response element-based reporter was regulated by G protein-coupled receptor kinase 2, but this did not affect the cell-surface abundance of the receptor. Our data suggest that constitutive and agonist-induced activity of D5R differentially regulates the activity and expression of proteins.

© 2014 FEBS.

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