The Drosophila G-protein-coupled receptor kinase homologue Gprk2 is required for egg morphogenesis

Development ◽  
1997 ◽  
Vol 124 (13) ◽  
pp. 2591-2602 ◽  
Author(s):  
L.E. Schneider ◽  
A.C. Spradling

G protein signaling is a widely utilized form of extracellular communication that is mediated by a family of serpentine receptors containing seven transmembrane domains. In sensory neurons, cardiac muscle and other tissues, G protein-coupled receptors are desensitized through phosphorylation by a family of kinases, the G protein-coupled receptor kinases (GRKs). Desensitization allows a cell to decrease its response to a given signal, in the continued presence of that signal. We have identified a Drosophila mutant, gprk2(6936) that disrupts expression of a putative member of the GRK family, the G protein-coupled receptor kinase 2 gene (Gprk2). This mutation affects Gprk2 gene expression in the ovaries and renders mutant females sterile. The mutant eggs contain defects in several anterior eggshell structures that are produced by specific subsets of migratory follicle cells. In addition, rare eggs that become fertilized display gross defects in embryogenesis. These observations suggest that developmental signals transduced by G protein-coupled receptors are regulated by receptor phosphorylation. Based on the known functions of G protein-coupled receptor kinases, we speculate that receptor desensitization assists cells that are migrating or undergoing shape changes to respond rapidly to changing external signals.

2011 ◽  
Vol 286 (22) ◽  
pp. 19259-19269 ◽  
Author(s):  
Il-Ha Lee ◽  
Sung-Hee Song ◽  
Craig R. Campbell ◽  
Sharad Kumar ◽  
David I. Cook ◽  
...  

The G protein-coupled receptor kinase (GRK2) belongs to a family of protein kinases that phosphorylates agonist-activated G protein-coupled receptors, leading to G protein-receptor uncoupling and termination of G protein signaling. GRK2 also contains a regulator of G protein signaling homology (RH) domain, which selectively interacts with α-subunits of the Gq/11 family that are released during G protein-coupled receptor activation. We have previously reported that kinase activity of GRK2 up-regulates activity of the epithelial sodium channel (ENaC) in a Na+ absorptive epithelium by blocking Nedd4-2-dependent inhibition of ENaC. In the present study, we report that GRK2 also regulates ENaC by a mechanism that does not depend on its kinase activity. We show that a wild-type GRK2 (wtGRK2) and a kinase-dead GRK2 mutant (K220RGRK2), but not a GRK2 mutant that lacks the C-terminal RH domain (ΔRH-GRK2) or a GRK2 mutant that cannot interact with Gαq/11/14 (D110AGRK2), increase activity of ENaC. GRK2 up-regulates the basal activity of the channel as a consequence of its RH domain binding the α-subunits of Gq/11. We further found that expression of constitutively active Gαq/11 mutants significantly inhibits activity of ENaC. Conversely, co-expression of siRNA against Gαq/11 increases ENaC activity. The effect of Gαq on ENaC activity is not due to change in ENaC membrane expression and is independent of Nedd4-2. These findings reveal a novel mechanism by which GRK2 and Gq/11 α-subunits regulate the activity ENaC.


2015 ◽  
Vol 290 (17) ◽  
pp. 10775-10790 ◽  
Author(s):  
Lingyong Li ◽  
Kristoff T. Homan ◽  
Sergey A. Vishnivetskiy ◽  
Aashish Manglik ◽  
John J. G. Tesmer ◽  
...  

1999 ◽  
Vol 162 (3) ◽  
pp. 401-408 ◽  
Author(s):  
CB Brenninkmeijer ◽  
SA Price ◽  
A Lopez Bernal ◽  
S Phaneuf

There is evidence for hormonal receptor desensitisation in human myometrium, but little is known about the mechanisms involved in the loss of myometrial response to agonists such as beta(2)-adrenergic agonists, prostaglandin gamma and oxytocin. It is well known that the receptors for these hormones are coupled to G-proteins. The first step of receptor desensitisation is the phosphorylation of activated receptors by a G-protein-coupled receptor kinase (GRK). GRKs are members of a multigene family and the various subtypes differ in their localisation, regulation and mode of action. We have used Western blotting and reverse transcription PCR to identify the GRKs present in human myometrium from pregnant and non-pregnant women as well as in cultured human myometrial cells. We have found that human myometrium expresses the GRK subtypes 2, 4gamma, 5 and 6. On the other hand, GRK3 and the isoforms GRK4alpha, beta and delta were not found in myometrial tissue. Our data indicate that GRK2 is only expressed in pregnant term myometrium and is not found in non-pregnant tissue. Moreover, GRK6 appears to be expressed at a much higher level in pregnant term tissue than in non-pregnant myometrium. Our observations suggest that GRK2 and GRK6 may contribute to the regulation of uterine contractility at term. Further work is necessary to determine whether GRKs and receptor desensitisation play a role in disorders of uterine contractility.


2014 ◽  
Vol 192 (5) ◽  
pp. 2186-2194 ◽  
Author(s):  
Vandana Singh ◽  
Sandeep K. Raghuwanshi ◽  
Nikia Smith ◽  
Elizabeth J. Rivers ◽  
Ricardo M. Richardson

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