Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel

Zoltán Oláh, Katalin Jósvay, László Pecze, Tamás Letoha, Norbert Babai, Dénes Budai, Ferenc Ötvös, Sándor Szalma, Csaba Vizler

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Ca2+ -loaded calmodulin normally inhibits multiple Ca2+ -channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+ -cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodullin drugs were noted here to inhibit Ca2+ -uptake via the vanifloid inducible Ca2+ channel/ inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+- uptake at μM concentrations: calmidazolium (broad range) ≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>'" fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca2+ or and-calmodulin drugs. Camstatin, a selective peptide blacker of calmodulin, inhibits vanilloid-induced Ca2+ -uptake in intact TRPV1+ cells, and suggests an extracellular site of inhibition. TRPV1+ inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by-various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca2+ -channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca2+ -channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca2+ -channels but not affecting motoneurons.

Original languageEnglish
Article numbere545
JournalPloS one
Volume2
Issue number6
DOIs
Publication statusPublished - Jun 20 2007

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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