Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 May 1;99(9):2087–2093. doi: 10.1172/JCI119381

G-protein-coupled receptor kinase activity is increased in hypertension.

R Gros 1, J L Benovic 1, C M Tan 1, R D Feldman 1
PMCID: PMC508038  PMID: 9151780

Abstract

Impaired vascular beta-adrenergic responsiveness may play an important role in the development and/or maintenance of hypertension. This defect has been associated with an alteration in receptor/guanine nucleotide regulatory protein (G-protein) interactions. However, the locus of this defect remains unclear. G-Protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues on G-protein-linked receptors in an agonist-dependent manner. GRK activation mediates reduced receptor responsiveness and impaired receptor/G-protein coupling. To determine whether the impairment in beta-adrenergic response in human hypertension might be associated with altered GRK activity, we studied lymphocytes from younger hypertensive subjects as compared with older and younger normotensive subjects. We assessed GRK activity by rhodopsin phosphorylation and GRK expression by immunoblot. GRK activity was significantly increased in lymphocytes from younger hypertensive subjects and paralleled an increase in GRK-2 (beta ARK-1) protein expression. In contrast, no alterations in cAMP-dependent kinase (A-kinase) activity or GRK-5/6 expression were noted. GRK activity was not increased in lymphocytes from older normotensive subjects who demonstrated a similar impairment in beta-adrenergic-mediated adenylyl cyclase activation. These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects. The increase in GRK activity may underlie the reduction in beta-adrenergic responsiveness characteristic of the hypertensive state.

Full Text

The Full Text of this article is available as a PDF (300.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barnes P. J. Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med. 1995 Sep;152(3):838–860. doi: 10.1164/ajrccm.152.3.7663795. [DOI] [PubMed] [Google Scholar]
  2. Benovic J. L., Mayor F., Jr, Staniszewski C., Lefkowitz R. J., Caron M. G. Purification and characterization of the beta-adrenergic receptor kinase. J Biol Chem. 1987 Jul 5;262(19):9026–9032. [PubMed] [Google Scholar]
  3. Brodde O. E., Daul A. E., O'Hara N., Khalifa A. M. Properties of alpha- and beta-adrenoceptors in circulating blood cells of patients with essential hypertension. J Cardiovasc Pharmacol. 1985;7 (Suppl 6):S162–S167. doi: 10.1097/00005344-198500076-00028. [DOI] [PubMed] [Google Scholar]
  4. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  5. Colucci W. S., Ribeiro J. P., Rocco M. B., Quigg R. J., Creager M. A., Marsh J. D., Gauthier D. F., Hartley L. H. Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization. Circulation. 1989 Aug;80(2):314–323. doi: 10.1161/01.cir.80.2.314. [DOI] [PubMed] [Google Scholar]
  6. De Blasi A., Parruti G., Sallese M. Regulation of G protein-coupled receptor kinase subtypes in activated T lymphocytes. Selective increase of beta-adrenergic receptor kinase 1 and 2. J Clin Invest. 1995 Jan;95(1):203–210. doi: 10.1172/JCI117641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Donoso L. A., Gregerson D. S., Smith L., Robertson S., Knospe V., Vrabec T., Kalsow C. M. S-antigen: preparation and characterization of site-specific monoclonal antibodies. Curr Eye Res. 1990 Apr;9(4):343–355. doi: 10.3109/02713689008999622. [DOI] [PubMed] [Google Scholar]
  8. Feldman R. D. A low-sodium diet corrects the defect in beta-adrenergic response in older subjects. Circulation. 1992 Feb;85(2):612–618. doi: 10.1161/01.cir.85.2.612. [DOI] [PubMed] [Google Scholar]
  9. Feldman R. D. Beta-adrenergic receptor alterations in hypertension--physiological and molecular correlates. Can J Physiol Pharmacol. 1987 Aug;65(8):1666–1672. doi: 10.1139/y87-261. [DOI] [PubMed] [Google Scholar]
  10. Feldman R. D. Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet. J Clin Invest. 1990 Mar;85(3):647–652. doi: 10.1172/JCI114487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Feldman R. D. Insulin-mediated sensitization of adenylyl cyclase activation. Br J Pharmacol. 1993 Dec;110(4):1640–1644. doi: 10.1111/j.1476-5381.1993.tb14013.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Feldman R. D., Lawton W. J., McArdle W. L. Low sodium diet corrects the defect in lymphocyte beta-adrenergic responsiveness in hypertensive subjects. J Clin Invest. 1987 Jan;79(1):290–294. doi: 10.1172/JCI112797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feldman R. D., Limbird L. E., Nadeau J., Robertson D., Wood A. J. Leukocyte beta-receptor alterations in hypertensive subjects. J Clin Invest. 1984 Mar;73(3):648–653. doi: 10.1172/JCI111255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Feldman R. D., Tan C. M., Chorazyczewski J. G protein alterations in hypertension and aging. Hypertension. 1995 Nov;26(5):725–732. doi: 10.1161/01.hyp.26.5.725. [DOI] [PubMed] [Google Scholar]
  15. Goldstein D. S. Plasma norepinephrine in essential hypertension. A study of the studies. Hypertension. 1981 Jan-Feb;3(1):48–52. doi: 10.1161/01.hyp.3.1.48. [DOI] [PubMed] [Google Scholar]
  16. Hausdorff W. P., Caron M. G., Lefkowitz R. J. Turning off the signal: desensitization of beta-adrenergic receptor function. FASEB J. 1990 Aug;4(11):2881–2889. [PubMed] [Google Scholar]
  17. Kiuchi K., Shannon R. P., Komamura K., Cohen D. J., Bianchi C., Homcy C. J., Vatner S. F., Vatner D. E. Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure. J Clin Invest. 1993 Mar;91(3):907–914. doi: 10.1172/JCI116312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Koch W. J., Rockman H. A., Samama P., Hamilton R. A., Bond R. A., Milano C. A., Lefkowitz R. J. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science. 1995 Jun 2;268(5215):1350–1353. doi: 10.1126/science.7761854. [DOI] [PubMed] [Google Scholar]
  19. Kong G., Penn R., Benovic J. L. A beta-adrenergic receptor kinase dominant negative mutant attenuates desensitization of the beta 2-adrenergic receptor. J Biol Chem. 1994 May 6;269(18):13084–13087. [PubMed] [Google Scholar]
  20. Laxminarayana D., Kammer G. M. Activation of type I protein kinase A during receptor-mediated human T lymphocyte activation. J Immunol. 1996 Jan 15;156(2):497–506. [PubMed] [Google Scholar]
  21. Lefkowitz R. J., Hausdorff W. P., Caron M. G. Role of phosphorylation in desensitization of the beta-adrenoceptor. Trends Pharmacol Sci. 1990 May;11(5):190–194. doi: 10.1016/0165-6147(90)90113-m. [DOI] [PubMed] [Google Scholar]
  22. Loudon R. P., Perussia B., Benovic J. L. Differentially regulated expression of the G-protein-coupled receptor kinases, betaARK and GRK6, during myelomonocytic cell development in vitro. Blood. 1996 Dec 15;88(12):4547–4557. [PubMed] [Google Scholar]
  23. Maisel A. S., Phillips C., Michel M. C., Ziegler M. G., Carter S. M. Regulation of cardiac beta-adrenergic receptors by captopril. Implications for congestive heart failure. Circulation. 1989 Sep;80(3):669–675. doi: 10.1161/01.cir.80.3.669. [DOI] [PubMed] [Google Scholar]
  24. Mills P. J., Berry C. C., Dimsdale J. E., Ziegler M. G., Nelesen R. A., Kennedy B. P. Lymphocyte subset redistribution in response to acute experimental stress: effects of gender, ethnicity, hypertension, and the sympathetic nervous system. Brain Behav Immun. 1995 Mar;9(1):61–69. doi: 10.1006/brbi.1995.1006. [DOI] [PubMed] [Google Scholar]
  25. Mills P. J., Ziegler M. G., Nelesen R. A., Kennedy B. P. The effects of the menstrual cycle, race, and gender on adrenergic receptors and agonists. Clin Pharmacol Ther. 1996 Jul;60(1):99–104. doi: 10.1016/S0009-9236(96)90172-1. [DOI] [PubMed] [Google Scholar]
  26. Naslund T., Silberstein D. J., Merrell W. J., Nadeau J. H., Wood A. J. Low sodium intake corrects abnormality in beta-receptor-mediated arterial vasodilation in patients with hypertension: correlation with beta-receptor function in vitro. Clin Pharmacol Ther. 1990 Jul;48(1):87–95. doi: 10.1038/clpt.1990.121. [DOI] [PubMed] [Google Scholar]
  27. Paietta E., Schwarzmeier J. D. beta-Adrenergic responsiveness of human peripheral lymphocytes after mitogenic transformation with phytohemagglutinin. Biochem Pharmacol. 1983 Oct 15;32(20):3085–3089. doi: 10.1016/0006-2952(83)90253-8. [DOI] [PubMed] [Google Scholar]
  28. Pippig S., Andexinger S., Daniel K., Puzicha M., Caron M. G., Lefkowitz R. J., Lohse M. J. Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors. J Biol Chem. 1993 Feb 15;268(5):3201–3208. [PubMed] [Google Scholar]
  29. Shasha S. M., Shasha U., Kristal B., Barzilai M., Steinberger O., Shkolnik T. Proliferative response of T lymphocytes to mitogenic lectins in essential hypertension. Nephron. 1991;58(4):413–417. doi: 10.1159/000186472. [DOI] [PubMed] [Google Scholar]
  30. Silver P. J., Michalak R. J., Kocmund S. M. Role of cyclic AMP protein kinase in decreased arterial cyclic AMP responsiveness in hypertension. J Pharmacol Exp Ther. 1985 Mar;232(3):595–601. [PubMed] [Google Scholar]
  31. Stiles G. L. Adrenergic receptor responsiveness and congestive heart failure. Am J Cardiol. 1991 May 6;67(12):13C–17C. doi: 10.1016/0002-9149(91)90068-v. [DOI] [PubMed] [Google Scholar]
  32. Ungerer M., Böhm M., Elce J. S., Erdmann E., Lohse M. J. Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation. 1993 Feb;87(2):454–463. doi: 10.1161/01.cir.87.2.454. [DOI] [PubMed] [Google Scholar]
  33. Venter C. P., Daya S., Joubert P. H., Strydom W. J. Ethnic differences in human lymphocytic cyclic AMP production after isoprenaline stimulation and propranolol blockade. Br J Clin Pharmacol. 1985 Feb;19(2):187–190. doi: 10.1111/j.1365-2125.1985.tb02630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES