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Adrbk1  -  adrenergic receptor kinase, beta 1

Mus musculus

Synonyms: Adrbk-1, Bark-1, Beta-ARK-1, Beta-adrenergic receptor kinase 1, G-protein-coupled receptor kinase 2, ...
 
 
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Disease relevance of Adrbk1

 

High impact information on Adrbk1

  • The PH domain in beta-adrenergic receptor kinase may be involved in binding to the beta gamma subunits of a trimeric G-protein [6].
  • Because increased amounts of beta ARK1 and diminished cardiac beta-adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of beta ARK in heart disease [7].
  • Animals overexpressing beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contractility in vivo, dampening of myocardial adenylyl cyclase activity, and reduced functional coupling of beta-adrenergic receptors [7].
  • Importantly, intermittent pressure overload caused diastolic dysfunction, altered beta-adrenergic receptor (betaAR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by betaAR kinase 1 to ligand-activated receptors [8].
  • Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression [9].
 

Chemical compound and disease context of Adrbk1

 

Biological context of Adrbk1

  • An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue [14].
  • OBJECTIVES: Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1) [15].
  • Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4 [16].
  • Normal cellular and whole heart function was restored in MLP(-/-) mice that express a cardiac-targeted transgene, which blocks the function of beta-adrenergic receptor (beta-AR) kinase-1 (betaARK1) [17].
  • The nucleotide sequences of rat GRK2 and GRK3 were aligned and conserved primers chosen for use in reverse transcription-polymerase chain reaction (RT-PCR) of S49 mRNA [3].
 

Anatomical context of Adrbk1

  • Receptor activation caused translocation of endogenous GRK2 to the plasma membrane [18].
  • However, the physiological relevance of reduced GRK2 levels in lymphocytes is not known [16].
  • Therefore, we postulated that GRK2 could be an inhibitor of the insulin signaling cascade leading to glucose transport in 3T3-L1 adipocytes [19].
  • A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility [20].
  • The level of GRK2 in leukocytes of patients after stroke, a neurological disorder with paralysis but without an autoimmune component, was similar to GRK2 levels in cells from healthy individuals [5].
 

Associations of Adrbk1 with chemical compounds

  • Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor [14].
  • Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine [21].
  • GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation [19].
  • In this study, we demonstrate that microinjection of anti-GRK2 antibody or siRNA against GRK2 increased insulin-stimulated insulin-responsive glucose transporter 4 (GLUT4) translocation, while adenovirus-mediated overexpression of wild-type or kinase-deficient GRK2 inhibited insulin-stimulated GLUT4 translocation as well as 2-deoxyglucose uptake [19].
  • Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial betaAR signaling and reduces betaARK1 levels in a specific and dose-dependent manner [22].
  • We conclude that (i) GRK2 negatively regulates basal and insulin-stimulated glycogen synthesis via a post-IR signaling mechanism, and (ii) GRK2 may contribute to reduced IR expression and function during chronic insulin exposure [23].
  • Together, our data revealed that distinct temporal phosphorylation of beta(2)AR on serine 355 and 356 by GRK2 plays a critical role for dictating receptor cellular events and signaling properties induced by Epi or NE in cardiomyocytes [24].
 

Physical interactions of Adrbk1

 

Enzymatic interactions of Adrbk1

  • The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors [26].
  • These results strongly suggest that beta AR kinase is able to phosphorylate and desensitize both stimulatory and inhibitory adenylate cyclase-coupled receptors, thus emerging as a general kinase that regulates the function of different receptors in an agonist-specific fashion [10].
 

Regulatory relationships of Adrbk1

  • A dominant negative GRK2 inhibited internalization whilst the protein kinase A (PKA) consensus site mutant MC2R (S208A) internalized normally [27].
  • This reciprocal regulation of betaARK1 documents a novel mechanism of ligand-induced betaAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure [22].
  • Somatostatin induces translocation of the beta-adrenergic receptor kinase and desensitizes somatostatin receptors in S49 lymphoma cells [10].
  • Taken together, these results indicate that through its RGS domain endogenous GRK2 functions as a negative regulator of insulin-stimulated glucose transport by interfering with Galphaq/11 signaling to GLUT4 translocation [19].
  • Moreover, they suggest that GRK2 plays an important role in vascular control and may represent a novel therapeutic target for hypertension [28].
 

Other interactions of Adrbk1

 

Analytical, diagnostic and therapeutic context of Adrbk1

  • In parallel, to determine the effect of chronic betaAR ligand treatment on the amounts of G protein receptor kinase-2 (GRK-2) and G proteins, we performed Western blotting on myocardial cytosolic and membrane proteins [30].
  • After attempts to ligate the four fragments of S49 cell GRK2 cDNA by using PCR proved unsuccessful, the intact cDNA was assembled by digesting the PCR products in the region of the overlaps and ligating them in a single step into pBlue-script SK(+) [3].
  • Fractionation of the kin- supernatant on molecular-sieve HPLC and DEAE-Sephacel results in a 50- to 100-fold purified beta-adrenergic receptor kinase preparation that is largely devoid of other protein kinase activities [31].
  • Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct animals [20].
  • CONCLUSIONS/INTERPRETATION: Sequence-based peptides derived from GRK2/3 have an antidiabetic effect demonstrated in three different animal models of Type 2 diabetes [32].

References

  1. Cardiac hypertrophy and altered beta-adrenergic signaling in transgenic mice that express the amino terminus of beta-ARK1. Keys, J.R., Greene, E.A., Cooper, C.J., Naga Prasad, S.V., Rockman, H.A., Koch, W.J. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  2. Exploring the role of the beta-adrenergic receptor kinase in cardiac disease using gene-targeted mice. Koch, W.J., Rockman, H.A. Trends Cardiovasc. Med. (1999) [Pubmed]
  3. Cloning of GRK2 cDNA from S49 murine lymphoma cells. Hughes, R.J., Anderson, K.L., Kiel, D., Insel, P.A. Am. J. Physiol. (1996) [Pubmed]
  4. Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Eckhart, A.D., Duncan, S.J., Penn, R.B., Benovic, J.L., Lefkowitz, R.J., Koch, W.J. Circ. Res. (2000) [Pubmed]
  5. G protein-coupled receptor kinase 2 in multiple sclerosis and experimental autoimmune encephalomyelitis. Vroon, A., Kavelaars, A., Limmroth, V., Lombardi, M.S., Goebel, M.U., Van Dam, A.M., Caron, M.G., Schedlowski, M., Heijnen, C.J. J. Immunol. (2005) [Pubmed]
  6. Structure of the pleckstrin homology domain from beta-spectrin. Macias, M.J., Musacchio, A., Ponstingl, H., Nilges, M., Saraste, M., Oschkinat, H. Nature (1994) [Pubmed]
  7. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Koch, W.J., Rockman, H.A., Samama, P., Hamilton, R.A., Bond, R.A., Milano, C.A., Lefkowitz, R.J. Science (1995) [Pubmed]
  8. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. Perrino, C., Naga Prasad, S.V., Mao, L., Noma, T., Yan, Z., Kim, H.S., Smithies, O., Rockman, H.A. J. Clin. Invest. (2006) [Pubmed]
  9. Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy. Freeman, K., Lerman, I., Kranias, E.G., Bohlmeyer, T., Bristow, M.R., Lefkowitz, R.J., Iaccarino, G., Koch, W.J., Leinwand, L.A. J. Clin. Invest. (2001) [Pubmed]
  10. Somatostatin induces translocation of the beta-adrenergic receptor kinase and desensitizes somatostatin receptors in S49 lymphoma cells. Mayor, F., Benovic, J.L., Caron, M.G., Lefkowitz, R.J. J. Biol. Chem. (1987) [Pubmed]
  11. Regulation of myocardial betaARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing alpha1B-adrenergic receptors. Iaccarino, G., Keys, J.R., Rapacciuolo, A., Shotwell, K.F., Lefkowitz, R.J., Rockman, H.A., Koch, W.J. J. Am. Coll. Cardiol. (2001) [Pubmed]
  12. Alternate coupling of receptors to Gs and Gi in pancreatic and submandibular gland cells. Luo, X., Zeng, W., Xu, X., Popov, S., Davignon, I., Wilkie, T.M., Mumby, S.M., Muallem, S. J. Biol. Chem. (1999) [Pubmed]
  13. Bbeta-adrenergic receptor kinase-1 levels in catecholamine-induced myocardial hypertrophy: regulation by beta- but not alpha1-adrenergic stimulation. Iaccarino, G., Dolber, P.C., Lefkowitz, R.J., Koch, W.J. Hypertension (1999) [Pubmed]
  14. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Rockman, H.A., Chien, K.R., Choi, D.J., Iaccarino, G., Hunter, J.J., Ross, J., Lefkowitz, R.J., Koch, W.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. Perrino, C., Naga Prasad, S.V., Patel, M., Wolf, M.J., Rockman, H.A. J. Am. Coll. Cardiol. (2005) [Pubmed]
  16. Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4. Vroon, A., Heijnen, C.J., Lombardi, M.S., Cobelens, P.M., Mayor, F., Caron, M.G., Kavelaars, A. J. Leukoc. Biol. (2004) [Pubmed]
  17. Cellular and functional defects in a mouse model of heart failure. Esposito, G., Santana, L.F., Dilly, K., Cruz, J.D., Mao, L., Lederer, W.J., Rockman, H.A. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  18. Beta-arrestin mediates desensitization and internalization but does not affect dephosphorylation of the thyrotropin-releasing hormone receptor. Jones, B.W., Hinkle, P.M. J. Biol. Chem. (2005) [Pubmed]
  19. GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. Usui, I., Imamura, T., Satoh, H., Huang, J., Babendure, J.L., Hupfeld, C.J., Olefsky, J.M. EMBO J. (2004) [Pubmed]
  20. Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice. Rockman, H.A., Choi, D.J., Akhter, S.A., Jaber, M., Giros, B., Lefkowitz, R.J., Caron, M.G., Koch, W.J. J. Biol. Chem. (1998) [Pubmed]
  21. Enhanced contractility and decreased beta-adrenergic receptor kinase-1 in mice lacking endogenous norepinephrine and epinephrine. Cho, M.C., Rao, M., Koch, W.J., Thomas, S.A., Palmiter, R.D., Rockman, H.A. Circulation (1999) [Pubmed]
  22. Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade. Iaccarino, G., Tomhave, E.D., Lefkowitz, R.J., Koch, W.J. Circulation (1998) [Pubmed]
  23. GRK2 negatively regulates glycogen synthesis in mouse liver FL83B cells. Shahid, G., Hussain, T. J. Biol. Chem. (2007) [Pubmed]
  24. Norepinephrine- and epinephrine-induced distinct beta2-adrenoceptor signaling is dictated by GRK2 phosphorylation in cardiomyocytes. Wang, Y., De Arcangelis, V., Gao, X., Ramani, B., Jung, Y.S., Xiang, Y. J. Biol. Chem. (2008) [Pubmed]
  25. A dominant negative mutant of the G protein-coupled receptor kinase 2 selectively attenuates adenosine A2 receptor desensitization. Mundell, S.J., Benovic, J.L., Kelly, E. Mol. Pharmacol. (1997) [Pubmed]
  26. Cloning, expression, and chromosomal localization of beta-adrenergic receptor kinase 2. A new member of the receptor kinase family. Benovic, J.L., Onorato, J.J., Arriza, J.L., Stone, W.C., Lohse, M., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Caron, M.G., Lefkowitz, R.J. J. Biol. Chem. (1991) [Pubmed]
  27. Agonist activated adrenocorticotropin receptor internalizes via a clathrin-mediated G protein receptor kinase dependent mechanism. Baig, A.H., Swords, F.M., Szaszák, M., King, P.J., Hunyady, L., Clark, A.J. Endocr. Res. (2002) [Pubmed]
  28. Vascular-targeted overexpression of G protein-coupled receptor kinase-2 in transgenic mice attenuates beta-adrenergic receptor signaling and increases resting blood pressure. Eckhart, A.D., Ozaki, T., Tevaearai, H., Rockman, H.A., Koch, W.J. Mol. Pharmacol. (2002) [Pubmed]
  29. In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function. Akhter, S.A., Eckhart, A.D., Rockman, H.A., Shotwell, K., Lefkowitz, R.J., Koch, W.J. Circulation (1999) [Pubmed]
  30. Treatment with inverse agonists enhances baseline atrial contractility in transgenic mice with chronic beta2-adrenoceptor activation. Nagaraja, S., Iyer, S., Liu, X., Eichberg, J., Bond, R.A. Br. J. Pharmacol. (1999) [Pubmed]
  31. Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor. Benovic, J.L., Strasser, R.H., Caron, M.G., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  32. Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes. Anis, Y., Leshem, O., Reuveni, H., Wexler, I., Ben Sasson, R., Yahalom, B., Laster, M., Raz, I., Ben Sasson, S., Shafrir, E., Ziv, E. Diabetologia (2004) [Pubmed]
 
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