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

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-α3 and NHE-2. Chronic treatment with an agonist increased the mRNA levels of the α2 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.

Keywords: GPCR; cAMP; constitutive activity; dopamine-1 receptor; dopamine-5 receptor.