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

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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 Ca2+ 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 Ca2+ influx and Ca2+ 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 Ca2+ channels. Using pharmacological approaches, we identified transient receptor potential canonical channel 3 (TRPC3) as a dominant contributor to Ca2+ 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 Ca2+ signal that perpetuates nocifensive responses. In contrast, Orai1 dominates as the downstream target of BK receptor activation and results in transient intracellular Ca2+ increases and abridged nocifensive responses.

Original languageEnglish (US)
JournalASN Neuro
Volume7
Issue number2
DOIs
StatePublished - Jan 1 2015

Keywords

  • Bradykinin
  • Endothelin
  • Inflammation
  • Pain
  • SOCE
  • Trigeminal neurons

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology

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