scholarly journals Functional Selectivity of Dopamine D1 Receptor Signaling: Retrospect and Prospect

2021 ◽  
Vol 22 (21) ◽  
pp. 11914
Author(s):  
Yang Yang
Keyword(s):  
G Protein ◽  
D1 Receptor ◽  
Mitogen Activated Protein Kinase ◽  
D1 Receptors ◽  
Research Progress ◽  
Research Front ◽  
Receptor Signaling ◽  
Functional Selectivity ◽  
Promising Strategy ◽  
Neurophysiological Studies

Research progress on dopamine D1 receptors indicates that signaling no longer is limited to G protein-dependent cyclic adenosine monophosphate phosphorylation but also includes G protein-independent β-arrestin-related mitogen-activated protein kinase activation, regulation of ion channels, phospholipase C activation, and possibly more. This review summarizes recent studies revealing the complexity of D1 signaling and its clinical implications, and suggests functional selectivity as a promising strategy for drug discovery to magnify the merit of D1 signaling. Functional selectivity/biased receptor signaling has become a major research front because of its potential to improve therapeutics through precise targeting. Retrospective pharmacological review indicated that many D1 ligands have some degree of mild functional selectivity, and novel compounds with extreme bias at D1 signaling were reported recently. Behavioral and neurophysiological studies inspired new methods to investigate functional selectivity and gave insight into the biased signaling of several drugs. Results from recent clinical trials also supported D1 functional selectivity signaling as a promising strategy for discovery and development of better therapeutics.

Role of oxidative stress in defective renal dopamine D1 receptor-G protein coupling and function in old Fischer 344 rats

2006 ◽  
Vol 291 (5) ◽  
pp. F945-F951 ◽  
Author(s):  
Riham Zein Fardoun ◽  
Mohammad Asghar ◽  
Mustafa Lokhandwala
Keyword(s):  
Oxidative Stress ◽  
G Protein ◽  
D1 Receptor ◽  
Serine Phosphorylation ◽  
D1 Receptors ◽  
Adult Rats ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Age Related ◽  
Old Rats

Aging is associated with an increase in oxidative stress. Previously, we have reported that dopamine failed to inhibit proximal tubular Na-K-ATPase and to promote sodium excretion in old rats (Beheray S, Kansra V, Hussain T, and Lokhandwala MF. Kidney Int 58: 712–720, 2000). This was due to uncoupling of dopamine D1 receptors from G proteins resulting from hyperphosphorylation of D1 receptors. The present study was designed to test the role of oxidative stress in the age-related decline in renal dopamine D1 receptor function. We observed that old animals had increased malondialdehyde (MDA) levels, a biomarker of oxidative stress, and decreased D1 receptor number and protein in the proximal tubules (PT) compared with adult rats. In old rats, there was increased G protein-coupled receptor kinase-2 (GRK-2) abundance, increased basal serine phosphorylation of D1 receptors, and defective D1 receptor-G protein coupling in PT membranes. Interestingly, supplementation with an antioxidant, tempol (1 mmol/l in drinking water for 15 days), lowered MDA levels and normalized D1 receptor number and protein in old rats to the level seen in adult rats. Furthermore, tempol decreased GRK-2 abundance and D1 receptor serine phosphorylation and restored D1 receptor-G protein coupling in PT of old rats. The functional consequence of these changes was the restoration of the natriuretic response to D1 receptor activation in tempol-supplemented old rats. Therefore, in old rats, tempol reduces oxidative stress and prevents GRK-2 membranous abundance and hyperphosphorylation of D1 receptors, resulting in restoration of D1 receptor-G protein coupling and the natriuretic response to SKF-38393. Thus tempol, by lowering oxidative stress, normalizes the age-related decline in dopamine receptor function.

Vanadium compounds cause activation of G protein-coupled receptor signaling

2020 ◽  
Author(s):  
Debbie C. Crans ◽  
Duaa Althumairy ◽  
Heide Murakami ◽  
B. George Barisas ◽  
Deborah Roess
Keyword(s):  
G Protein ◽  
Receptor Signaling ◽  
G Protein Coupled Receptor ◽  
Vanadium Compounds ◽  
G Protein Coupled

scholarly journals Targeted Expression of the Class II Phosphoinositide 3-Kinase in Drosophila melanogaster Reveals Lipid Kinase-Dependent Effects on Patterning and Interactions with Receptor Signaling Pathways

2004 ◽  
Vol 24 (2) ◽  
pp. 796-808 ◽  
Author(s):  
Lindsay K. MacDougall ◽  
Mary Elizabeth Gagou ◽  
Sally J. Leevers ◽  
Ernst Hafen ◽  
Michael D. Waterfield
Keyword(s):  
Drosophila Melanogaster ◽  
Signaling Pathways ◽  
Egf Receptor ◽  
Adaptor Protein ◽  
Class Ii ◽  
Notch Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Class I ◽  
Wing Venation ◽  
Receptor Signaling

ABSTRACT Phosphoinositide 3-kinases (PI3Ks) can be divided into three distinct classes (I, II, and III) on the basis of their domain structures and the lipid signals that they generate. Functions have been assigned to the class I and class III enzymes but have not been established for the class II PI3Ks. We have obtained the first evidence for a biological function for a class II PI3K by expressing this enzyme during Drosophila melanogaster development and by using deficiencies that remove the endogenous gene. Wild-type and catalytically inactive PI3K_68D transgenes have opposite effects on the number of sensory bristles and on wing venation phenotypes induced by modified epidermal growth factor (EGF) receptor signaling. These results indicate that the endogenous PI3K_68D may act antagonistically to the EGF receptor-stimulated Ras-mitogen-activated protein kinase pathway and downstream of, or parallel to, the Notch receptor. A class II polyproline motif in PI3K_68D can bind the Drk adaptor protein in vitro, primarily via the N-terminal SH3 domain of Drk. Drk may thus be important for the localization of PI3K_68D, allowing it to modify signaling pathways downstream of cell surface receptors. The phenotypes obtained are markedly distinct from those generated by expression of the Drosophila class I PI3K, which affects growth but not pattern formation.

G-protein-coupled-receptor activation of the smooth muscle calponin gene

2001 ◽  
Vol 357 (2) ◽  
pp. 587-592 ◽  
Author(s):  
Nickolai O. DULIN ◽  
Sergei N. ORLOV ◽  
Chad M. KITCHEN ◽  
Tatyana A. VOYNO-YASENETSKAYA ◽  
Joseph M. MIANO
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
G Protein ◽  
Transcriptional Activation ◽  
Fold Increase ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinase ◽  
G Protein Coupled

A hallmark of cultured smooth muscle cells (SMCs) is the rapid down-regulation of several lineage-restricted genes that define their in vivo differentiated phenotype. Identifying factors that maintain an SMC differentiated phenotype has important implications in understanding the molecular underpinnings governing SMC differentiation and their subversion to an altered phenotype in various disease settings. Here, we show that several G-protein coupled receptors [α-thrombin, lysophosphatidic acid and angiotensin II (AII)] increase the expression of smooth muscle calponin (SM-Calp) in rat and human SMC. The increase in SM-Calp protein appears to be selective for G-protein-coupled receptors as epidermal growth factor was without effect. Studies using AII showed a 30-fold increase in SM-Calp protein, which was dose- and time-dependent and mediated by the angiotensin receptor-1 (AT1 receptor). The increase in SM-Calp protein with AII was attributable to transcriptional activation of SM-Calp based on increases in steady-state SM-Calp mRNA, increases in SM-Calp promoter activity and complete abrogation of protein induction with actinomycin D. To examine the potential role of extracellular signal-regulated kinase (Erk1/2), protein kinase B, p38 mitogen-activated protein kinase and protein kinase C in AII-induced SM-Calp, inhibitors to each of the signalling pathways were used. None of these signalling molecules appears to be crucial for AII-induced SM-Calp expression, although Erk1/2 may be partially involved. These results identify SM-Calp as a target of AII-mediated signalling, and suggest that the SMC response to AII may incorporate a novel activity of SM-Calp.

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