BIOMAT Database Logo BIOMAT Database Logo

G protein-coupled receptor kinase-2 constitutively regulates D2 dopamine receptor expression and signaling independently of receptor phosphorylation. 2009

Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
Molecular Neuropharmacology Section, NINDS, National Institutes of Health, Bethesda, Maryland 20892-9405, USA.

We investigated the regulatory effects of GRK2 on D(2) dopamine receptor signaling and found that this kinase inhibits both receptor expression and functional signaling in a phosphorylation-independent manner, apparently through different mechanisms. Overexpression of GRK2 was found to suppress receptor expression at the cell surface and enhance agonist-induced internalization, whereas short interfering RNA knockdown of endogenous GRK2 led to an increase in cell surface receptor expression and decreased agonist-mediated endocytosis. These effects were not due to GRK2-mediated phosphorylation of the D(2) receptor as a phosphorylation-null receptor mutant was regulated similarly, and overexpression of a catalytically inactive mutant of GRK2 produced the same effects. The suppression of receptor expression is correlated with constitutive association of GRK2 with the receptor complex as we found that GRK2 and several of its mutants were able to co-immunoprecipitate with the D(2) receptor. Agonist pretreatment did not enhance the ability of GRK2 to co-immunoprecipitate with the receptor. We also found that overexpression of GRK2 attenuated the functional coupling of the D(2) receptor and that this activity required the kinase activity of GRK2 but did not involve receptor phosphorylation, thus suggesting the involvement of an additional GRK2 substrate. Interestingly, we found that the suppression of functional signaling also required the G betagamma binding activity of GRK2 but did not involve the GRK2 N-terminal RH domain. Our results suggest a novel mechanism by which GRK2 negatively regulates G protein-coupled receptor signaling in a manner that is independent of receptor phosphorylation.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000242 Cyclic AMP An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH. Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015971 Gene Expression Regulation, Enzymologic Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis. Enzymologic Gene Expression Regulation,Regulation of Gene Expression, Enzymologic,Regulation, Gene Expression, Enzymologic

Related Publications

Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor.
August 2009, The Journal of biological chemistry,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
Drosophila G-protein-coupled receptor kinase 2 regulates cAMP-dependent Hedgehog signaling.
January 2012, Development (Cambridge, England),
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
The D1 dopamine receptor is constitutively phosphorylated by G protein-coupled receptor kinase 4.
March 2006, Molecular pharmacology,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
G protein-coupled receptor kinase-2 confers isoform-specific calcium sensitivity to dopamine D2 receptor desensitization.
November 2021, FASEB journal : official publication of the Federation of American Societies for Experimental Biology,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
Phosphorylation-independent regulation of metabotropic glutamate receptor signaling by G protein-coupled receptor kinase 2.
July 2002, The Journal of biological chemistry,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
G Protein-Coupled Receptor Kinase 2 Selectively Enhances β-Arrestin Recruitment to the D2 Dopamine Receptor through Mechanisms That Are Independent of Receptor Phosphorylation.
October 2023, Biomolecules,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
Constitutive phosphorylation by protein kinase C regulates D1 dopamine receptor signaling.
December 2010, Journal of neurochemistry,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
Arrestin-dependent but G-protein coupled receptor kinase-independent uncoupling of D2-dopamine receptors.
October 2013, Journal of neurochemistry,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits.
January 2006, Molecular biology of the cell,
Yoon Namkung, and Concetta Dipace, and Eneko Urizar, and Jonathan A Javitch, and David R Sibley
Signaling-Biased and Constitutively Active Dopamine D2 Receptor Variant.
June 2021, ACS chemical neuroscience,
Copied contents to your clipboard!