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Beta-arrestin2 enhances beta2-adrenergic receptor-mediated nuclear translocation of ERK

Hiroyuki Kobayashi1, Yusuke Narita, Motohiro Nishida

  • 1Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.

Cellular Signalling
|July 26, 2005
PubMed

Insights

Beta-arrestin2 enhances the nuclear localization of extracellular signal-regulated kinase (ERK) in beta-adrenergic receptor (betaAR) signaling. This beta-arrestin2-mediated mechanism is dependent on Gbetagamma and the beta2AR carboxyl-terminal region.

Area of Science:

  • Cellular signaling pathways
  • G protein-coupled receptor (GPCR) regulation
  • Molecular cell biology

Background:

  • Beta-arrestins are known to mediate the desensitization and internalization of beta-adrenergic receptors (betaARs).
  • Beta-arrestins also function as crucial scaffold proteins within the extracellular signal-regulated kinase (ERK) cascade.
  • The specific role of beta-arrestin2 in betaAR-mediated ERK signaling pathways requires further elucidation.

Purpose of the Study:

  • To investigate the role of beta-arrestin2 in beta-adrenergic receptor (betaAR)-mediated extracellular signal-regulated kinase (ERK) signaling.
  • To determine the specific mechanisms by which beta-arrestin2 influences ERK activation and localization.
  • To explore the involvement of Gbetagamma subunits and receptor structure in beta-arrestin2-mediated signaling.

Main Methods:

  • Utilized COS-7 cells co-expressing beta1AR or beta2AR with or without beta-arrestin2.
  • Stimulated cells with isoproterenol to activate betaARs.
  • Assessed cytoplasmic and nuclear ERK activation.
  • Employed pertussis toxin treatment and Gbetagamma blockade to investigate signaling pathways.
  • Generated chimeric receptors to examine the role of the carboxyl-terminal region.

Main Results:

  • Isoproterenol equally activated cytoplasmic and nuclear ERK in cells expressing beta1AR or beta2AR.
  • Co-expression of beta-arrestin2 significantly enhanced nuclear ERK activity in beta2AR-expressing cells, but not in beta1AR-expressing cells.
  • Pertussis toxin and Gbetagamma blockade inhibited beta-arrestin2-enhanced nuclear ERK activation, indicating a Gbetagamma-dependent mechanism.
  • A beta2AR mutant lacking the carboxyl-terminal region lost the beta-arrestin2-promoted nuclear translocation of ERK.

Conclusions:

  • Beta-arrestin2 plays a critical role in promoting the nuclear localization of ERK in response to beta2AR stimulation.
  • This nuclear translocation is dependent on Gbetagamma signaling and the specific recruitment of beta-arrestin2 to the beta2AR carboxyl-terminal region.
  • The findings highlight the distinct roles of beta-arrestin isoforms and receptor domains in regulating intracellular signaling cascades.

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