Inhibition of depolarization-induced [3H]noradrenaline release from SH-SY5Y human neuroblastoma cells by some second-generation H1 receptor antagonists through blockade of store-operated Ca2+ channels (SOCs)

Maurizio Taglialatela, Agnese Secondo, Angela Fresi, Barbara Rosati, Anna Pannaccione, Pasqualina Castaldo, Giovanna Giorgio, Enzo Wanke, Lucio Annunziato

Research output: Contribution to journalArticle

Abstract

In the present study, the effect of the blockade of membrane calcium channels activated by intracellular Ca2+ store depletion on basal and depolarization-induced [3H]norepinephrine ([3H]NE) release from SH-SY5Y human neuroblastoma cells was examined. The second-generation H1 receptor blockers astemizole, terfenadine, and loratadine, as well as the first-generation compound hydroxyzine, inhibited [3H]NE release induced by high extracellular K+ concentration ([K+]e) depolarization in a concentration-dependent manner (the ic50s were 2.3, 1.7, 4.8, and 9.4 μM, respectively). In contrast, the more hydrophilic second-generation H1 receptor blocker cetirizine was completely ineffective (0.1-30 μM). The inhibition of high [K+]e-induced [3H]NE release by H1 receptor blockers seems to be related to their ability to inhibit Ca2+ channels activated by Cai 2+ store depletion (SOCs). In fact, astemizole, terfenadine, loratadine, and hydroxyzine, but not cetirizine, displayed a dose-dependent inhibitory action on the increase in intracellular Ca2+ concentrations ([Ca2+]i) obtained with extracellular Ca2+ reintroduction after Cai 2+ store depletion with thapsigargin (1 μM), an inhibitor of the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA) pump. The rank order of potency for SOC inhibition by these compounds closely correlated with their inhibitory properties on depolarization-induced [3H]NE release from SH-SY5Y human neuroblastoma cells. Nimodipine (1 μM) plus ω-conotoxin (100 nM) did not interfere with the present model for SOC activation. In addition, the inhibition of depolarization-induced [3H]NE release does not seem to be attributable to the blockade of the K+ currents carried by the K+ channels encoded by the human Ether-a-Gogo Related Gene (IHERG) by these antihistamines. In fact, whole-cell voltage-clamp experiments revealed that the ic50 for astemizole-induced hERG blockade is about 300-fold lower than that for the inhibition of high K+-induced [3H]NE release. Furthermore, current-clamp experiments in SH-SY5Y cells showed that concentrations of astemizole (3 μM) which were effective in preventing depolarization-induced [3H]NE release were unable to interfere with the cell membrane potential under depolarizing conditions (100 mM [K+]e), suggesting that hERG K+ channels do not contribute to membrane potential control during exposure to elevated [K+]e. Collectively, the results of the present study suggest that, in SH-SY5Y human neuroblastoma cells, the inhibition of SOCs by some second-generation antihistamines can prevent depolarization-induced neurotransmitter release.

Original languageEnglish
Pages (from-to)1229-1238
Number of pages10
JournalBiochemical Pharmacology
Volume62
Issue number9
DOIs
Publication statusPublished - Nov 1 2001

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Keywords

  • Ca channels activated by Ca store depletion
  • Depolarization-induced norepinephrine release
  • hERG K channels
  • Long QT syndrome
  • Second-generation antihistamines
  • SH-SY5Y human neuroblastoma cells

ASJC Scopus subject areas

  • Pharmacology

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