A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation - PubMed (original) (raw)

A small region of the beta-adrenergic receptor is selectively involved in its rapid regulation

W P Hausdorff et al. Proc Natl Acad Sci U S A. 1991.

Abstract

Plasma membrane receptors that couple to guanine nucleotide-binding regulatory proteins (G proteins) undergo a variety of rapid (minutes) and longer term (hours) regulatory processes induced by ligands. For the beta 2-adrenergic receptor (beta 2AR), the rapid processes include functional desensitization, mediated by phosphorylation of the receptor by the cAMP-dependent protein kinase and the beta-adrenergic receptor kinase, as well as a loss of hydrophilic ligand binding proposed to represent sequestration of receptors into a cellular compartment distinct from the plasma membrane. The slower processes include beta 2AR down-regulation (i.e., a decrease in the total cellular complement of receptors). It is not yet known whether beta 2AR phosphorylation and/or sequestration are prerequisites for down-regulation of the receptor. Like other G protein-coupled receptors, the beta 2AR molecule spans the plasma membrane seven times, and the cytoplasmic carboxyl-terminal domain has been proposed to contain molecular determinants for each of these regulatory processes. We replaced four serine and threonine residues located within a 10-amino acid segment of this domain of beta 2AR and thereby prevented agonist-promoted phosphorylation, sequestration, and rapid desensitization of the adenylyl cyclase response. In contrast, these mutations did not affect functional coupling to the stimulatory G protein Gs or long-term down-regulation. These findings thus define a small, hitherto unappreciated region of the receptor molecule that may selectively subserve its rapid regulation. In addition, with the demonstration that beta 2AR does not have to be phosphorylated or sequestered in order to enter the down-regulation pathway, the results suggest that the classical receptor endocytosis model may not be appropriate for beta 2AR regulation.

PubMed Disclaimer

Similar articles

• Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.
  Liggett SB, Freedman NJ, Schwinn DA, Lefkowitz RJ. Liggett SB, et al. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665-9. doi: 10.1073/pnas.90.8.3665. Proc Natl Acad Sci U S A. 1993. PMID: 8386380 Free PMC article.
• Mutations of the human beta 2-adrenergic receptor that impair coupling to Gs interfere with receptor down-regulation but not sequestration.
  Campbell PT, Hnatowich M, O'Dowd BF, Caron MG, Lefkowitz RJ, Hausdorff WP. Campbell PT, et al. Mol Pharmacol. 1991 Feb;39(2):192-8. Mol Pharmacol. 1991. PMID: 1847493
• Beta-adrenergic receptor-coupled adenylate cyclase. Biochemical mechanisms of regulation.
  Sibley DR, Lefkowitz RJ. Sibley DR, et al. Mol Neurobiol. 1987 Spring-Summer;1(1-2):121-54. doi: 10.1007/BF02935266. Mol Neurobiol. 1987. PMID: 2855789 Review.
• Molecular mechanisms of receptor desensitization using the beta-adrenergic receptor-coupled adenylate cyclase system as a model.
  Sibley DR, Lefkowitz RJ. Sibley DR, et al. Nature. 1985 Sep 12-18;317(6033):124-9. doi: 10.1038/317124a0. Nature. 1985. PMID: 2993919 Review.

Cited by

• A common intracellular allosteric binding site for antagonists of the CXCR2 receptor.
  Salchow K, Bond ME, Evans SC, Press NJ, Charlton SJ, Hunt PA, Bradley ME. Salchow K, et al. Br J Pharmacol. 2010 Apr;159(7):1429-39. doi: 10.1111/j.1476-5381.2009.00623.x. Epub 2010 Mar 3. Br J Pharmacol. 2010. PMID: 20233217 Free PMC article.
• Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.
  Liggett SB, Freedman NJ, Schwinn DA, Lefkowitz RJ. Liggett SB, et al. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3665-9. doi: 10.1073/pnas.90.8.3665. Proc Natl Acad Sci U S A. 1993. PMID: 8386380 Free PMC article.
• Impaired activation of adenylyl cyclase in lung of the Basenji-greyhound model of airway hyperresponsiveness: decreased numbers of high affinity beta-adrenoceptors.
  Emala CW, Aryana A, Hirshman CA. Emala CW, et al. Br J Pharmacol. 1996 Aug;118(8):2009-16. doi: 10.1111/j.1476-5381.1996.tb15637.x. Br J Pharmacol. 1996. PMID: 8864536 Free PMC article.
• Insulation of a G protein-coupled receptor on the plasmalemmal surface of the pancreatic acinar cell.
  Roettger BF, Rentsch RU, Hadac EM, Hellen EH, Burghardt TP, Miller LJ. Roettger BF, et al. J Cell Biol. 1995 Aug;130(3):579-90. doi: 10.1083/jcb.130.3.579. J Cell Biol. 1995. PMID: 7622559 Free PMC article.
• Regulatory mechanisms that modulate signalling by G-protein-coupled receptors.
  Böhm SK, Grady EF, Bunnett NW. Böhm SK, et al. Biochem J. 1997 Feb 15;322 ( Pt 1)(Pt 1):1-18. doi: 10.1042/bj3220001. Biochem J. 1997. PMID: 9078236 Free PMC article. Review.

References

1. 1. Mol Pharmacol. 1991 Feb;39(2):192-8 - PubMed
2. 1. J Mol Biol. 1978 Mar 25;120(1):97-120 - PubMed
3. 1. J Biol Chem. 1989 Nov 25;264(33):19535-9 - PubMed
4. 1. Mol Pharmacol. 1989 Jan;35(1):132-8 - PubMed
5. 1. J Biol Chem. 1987 Oct 15;262(29):14282-8 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Atypon
  • Europe PubMed Central
  • PubMed Central