The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain

Arriza, Jeffrey L.; Dawson, Ted M.; Simerly, Richard B.; Martin, Lee J.; Caron, Marc G.; Snyder, Solomon H.; Lefkowitz, Robert J.

doi:10.1523/jneurosci.12-10-04045.1992

Cited by 190 publications

(103 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Western Blot Analysis of GRK 2-The expression of bovine GRK2 in transfected COS-7 cells was assessed as previously described (9) using an antiserum raised against a glutathione S-transferase fusion protein encoding residues 467-688 of rat GRK3 (27).…”

Section: Methodsmentioning

confidence: 99%

Characterization of the Phosphorylation Sites Involved in G Protein-coupled Receptor Kinase- and Protein Kinase C-mediated Desensitization of the α1B-Adrenergic Receptor

Diviani¹,

Lattion²,

Cotecchia³

1997

Journal of Biological Chemistry

117

View full text Add to dashboard Cite

Catecholamines as well as phorbol esters can induce the phosphorylation and desensitization of the ␣ 1B -adrenergic receptor (␣ 1B AR). In this study, phosphoamino acid analysis of the phosphorylated ␣ 1B AR revealed that both epinephrine-and phorbol ester-induced phosphorylation predominantly occurs at serine residues of the receptor. The findings obtained with receptor mutants in which portions of the C-tail were truncated or deleted indicated that a region of 21 amino acids (393-413) of the carboxyl terminus including seven serines contains the main phosphorylation sites involved in agonist-as well as phorbol ester-induced phosphorylation and desensitization of the ␣ 1B AR. To identify the serines invoved in agonist-versus phorbol ester-dependent regulation of the receptor, two different strategies were adopted, the seven serines were either substituted with alanine or reintroduced into a mutant lacking all of them. Desensitization is a general regulatory phenomenon of G protein-coupled receptors resulting in the attenuation of the receptor-mediated response. Two major patterns of desensitization referred to as homologous and heterologous desensitization can be distinguished. Homologous desensitization is defined as a rapid loss of responsiveness for a receptor repeatedly exposed to its specific agonist, whereas in heterologous desensitization stimulation of a receptor by an agonist can attenuate the response mediated by other receptors eliciting similar cellular effects (1).In the G protein-coupled receptor family (2), receptor desensitization has been extensively characterized for rhodopsin mediating phototransduction in retinal rod cells and for the ␤ 2 -adrenergic receptor (␤ 2 AR) 1 which mediates catecholamineinduced stimulation of adenylyl cyclase. The second messengerdependent cAMP-dependent protein kinase can phosphorylate and desensitize the ␤ 2 AR both in response to its agonist as well as to other agents increasing the cellular content of cAMP. On the other hand, a prominent role in homologous desensitization of rhodopsin and ␤ 2 AR is played by the second messengerindependent rhodopsin kinase (3) and ␤-adrenergic receptor kinase (␤ARK) (4), respectively. Once the receptor is occupied by the agonist, it is recognized by the kinase and becomes phosphorylated. The subsequent uncoupling of the receptor and G protein is then mediated by arrestin proteins, which specifically bind to the phosphorylated receptor (5, 6). Rhodopsin kinase and ␤ARK are members of the newly discovered family of G protein-coupled receptor kinases (GRK) (7). These protein kinases have the unique ability to recognize and phosphorylate their G protein-coupled receptor substrates predominantly in their active (i.e. agonist-occupied) conformations. Recently, we have provided evidence that the ␣ 1B AR coupled to Gq-mediated activation of phospholipase C can be phosphorylated by at least two types of protein kinases, a protein kinase C (PKC) upon its stimulation by phorbol esters (8) and protein kinases belonging to the GRK family o...

show abstract

Section: Methodsmentioning

confidence: 99%

Characterization of the Phosphorylation Sites Involved in G Protein-coupled Receptor Kinase- and Protein Kinase C-mediated Desensitization of the α1B-Adrenergic Receptor

Diviani¹,

Lattion²,

Cotecchia³

1997

Journal of Biological Chemistry

117

View full text Add to dashboard Cite

show abstract

“…βARK1 is usually more highly expressed and, in addition, very high levels of this kinase are found in monocytes and granulocytes [94]. βARK1\2 are also found in neuronal cell bodies in the brain and in pre-synaptic and post-synaptic locations, with the latter predominating [95]. This suggests that βARK1\2 are likely to function in the desensitization of many receptors, especially those activated at synapses.…”

Section: Figure 5 Molecular Architecture Of Arrestinsmentioning

confidence: 99%

“…This suggests that βARK1\2 are likely to function in the desensitization of many receptors, especially those activated at synapses. Since βARK1\2 mediate homologous desensitization of the β # -AR to high concentrations of agonists, they are most likely to participate in the homologous desensitization of receptors that are exposed to high concentrations of agonists, a hypothesis that is supported by the synaptic localization of these proteins [95]. Demonstration of the co-localization of the GRKs and GPCRs is necessary in order to determine if these kinases are capable of regulating receptors under physiological circumstances.…”

Section: Figure 5 Molecular Architecture Of Arrestinsmentioning

confidence: 99%

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Böhm

Grady

Bunnett

1997

Biochemical Journal

477

322

View full text Add to dashboard Cite

The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and downregulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from

show abstract

“…Two arrestin subtypes, arrestin2 and arrestin3, are ubiquitous [6,13,31,32]. Five out of seven GRK subtypes, GRK2, 3, 4, 5, and 6, are widely expressed in the brain with largely overlapping cellular distribution [5,10,13,32,89]. In vitro data demonstrate that most GPCR subtypes can be phosphorylated by several GRKs [71,94] and bind both arrestins equally well [33,59,94].…”

Section: Introductionmentioning

confidence: 99%

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Bychkov

Joyce

et al. 2008

Neurobiology of Aging

View full text Add to dashboard Cite

Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at post mortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

show abstract

The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain

Cited by 190 publications

References 27 publications

Characterization of the Phosphorylation Sites Involved in G Protein-coupled Receptor Kinase- and Protein Kinase C-mediated Desensitization of the α1B-Adrenergic Receptor

Characterization of the Phosphorylation Sites Involved in G Protein-coupled Receptor Kinase- and Protein Kinase C-mediated Desensitization of the α1B-Adrenergic Receptor

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Contact Info

Product

Resources

About