The 27-kDa heat shock protein confers cytoprotective effects through a β2-adrenergic receptor agonist-initiated complex with β-arrestin

Lalida Rojanathammanee, Erin B. Harmon, Laurel A. Grisanti, Piyarat Govitrapong, Manuchair Ebadi, Bryon D. Grove, Masaru Miyagi, James E. Porter

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Heat shock proteins represent an emerging model for the coordinated, multistep regulation of apoptotic signaling events. Although certain aspects of the biochemistry associated with heat shock protein cytoprotective effects are known, little information is found describing the regulation of heat shock protein responses to harmful stimuli. During screening for non-canonical (β adrenergic receptor signaling pathways in human urothelial cells, using mass spectroscopy techniques, an agonist-dependent interaction with β-arrestin and the 27-kDa heat shock protein was observed in vitro. Formation of this β-arrestin/Hsp27 complex in response to the selective β adrenergic receptor agonist isoproterenol, was subsequently confirmed in situ by immunofluorescent colocalization studies. Radioligand binding techniques characterized a homogeneous population of the β2 adrenergic receptor subtype expressed on these cells. Using terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, immunoblot analysis and quantitation of caspase-3 activity to detect apoptosis, preincubation of these cells with isoproterenol was found to be sufficient for protection against programmed cell death initiated by staurosporine. RNA interference strategies confirmed the necessity for Hsp27 as well as both 3-arrestin isoforms to confer this cytoprotective consequence of (β adrenergic receptor activation in this cell model. As a result, these studies represent the first description of an agonist-dependent relationship between a small heat shock protein and β-arrestin to form a previously unknown antiapoptotic "signalosome."

Original languageEnglish (US)
Pages (from-to)855-865
Number of pages11
JournalMolecular pharmacology
Volume75
Issue number4
DOIs
StatePublished - Apr 1 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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