Divergence in endothelin-1- and bradykinin-activated store-operated calcium entry in afferent sensory neurons

Kalina Szteyn, Ruben Gomez, Kelly A Berg, Nathaniel Jeske

Research output: Contribution to journalArticle

7 Scopus citations


Endothelin-1 (ET-1) and bradykinin (BK) are endogenous peptides that signal through Gαq/11-protein coupled receptors (GPCRs) to produce nociceptor sensitization and pain. Both peptides activate phospholipase C to stimulate Ca(2+) accumulation, diacylglycerol production, and protein kinase C activation and are rapidly desensitized via a G-protein receptor kinase 2-dependent mechanism. However, ET-1 produces a greater response and longer lasting nocifensive behavior than BK in multiple models, indicating a potentially divergent signaling mechanism in primary afferent sensory neurons. Using cultured sensory neurons, we demonstrate significant differences in both Ca(2+) influx and Ca(2+) release from intracellular stores following ET-1 and BK treatments. As intracellular store depletion may contribute to the regulation of other signaling cascades downstream of GPCRs, we concentrated our investigation on store-operated Ca(2+) channels. Using pharmacological approaches, we identified transient receptor potential canonical channel 3 (TRPC3) as a dominant contributor to Ca(2+) influx subsequent to ET-1 treatment. On the other hand, BK treatment stimulated Orai1 activation, with only minor input from TRPC3. Taken together, data presented here suggest that ET-1 signaling targets TRPC3, generating a prolonged Ca(2+) signal that perpetuates nocifensive responses. In contrast, Orai1 dominates as the downstream target of BK receptor activation and results in transient intracellular Ca(2+) increases and abridged nocifensive responses.

Original languageEnglish (US)
JournalASN Neuro
Issue number2
StatePublished - Mar 1 2015


  • bradykinin
  • endothelin
  • inflammation
  • pain
  • SOCE
  • trigeminal neurons

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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