Modulation of bradykinin signaling by EP24.15 and EP24.16 in cultured trigeminal ganglia

Nathaniel A. Jeske, Kelly A. Berg, Joanne C. Cousins, Emer S. Ferro, William P. Clarke, Marc J. Glucksman, James L. Roberts

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Metalloendopeptidases expressed in neural tissue are characterized in terms of their neuropeptide substrates. One such neuropeptide, bradykinin (BK), is an important inflammatory mediator that activates the type-2 BK receptor (B2R) on the terminal endings of specialized pain-sensing neurons known as nociceptors. Among several metalloendopeptidases that metabolize and inactivate BK, EP24.15 and EP24.16 are known to associate with the plasma membrane in several immortalized cell lines. Potentially, the colocalization of EP24.15/16 and B2R at plasma membrane microdomains known as lipid rafts in a physiologically relevant nociceptive system would allow for discrete, peptidase regulation of BK signaling. Western blot analysis of crude subcellular fractions and lipid raft preparations of cultured rat trigeminal ganglia demonstrate similar expression profiles between EP24.15/16 and B2R on a subcellular level. Furthermore, the treatment of primary cultures of trigeminal ganglia with inhibitors of EP24.15/16 led to the potentiation of several bradykinin-induced events that occur downstream of B2R activation. EP24.15/16 inhibition by N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-AlalTyr-p-aminobenzoate (cFP) resulted in a 1000-fold increase in B2R sensitivity to BK as measured by inositol phosphate accumulation. In addition, cFP treatment resulted in a 31.1 ± 5.0% potentiation of the ability of BK to inhibit protein kinase B (Akt) activity. Taken together, these data demonstrate that EP24.15/16 modulate intracellular, peptidergic signaling cascades through B2R in a physiologically relevant nociceptive system.

Original languageEnglish (US)
Pages (from-to)13-21
Number of pages9
JournalJournal of neurochemistry
Volume97
Issue number1
DOIs
StatePublished - Apr 2006

Keywords

  • Bradykinin
  • Lipid raft
  • Microdomain
  • Trigeminal

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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