Multiple channel interactions explain the protection of sympathetic neurons from apoptosis induced by nerve growth factor deprivation

Shuli Xia, Patricia A. Lampe, Mohanish Deshmukh, Aizhen Yang, Barry S. Brown, Steve M. Rothman, Eugene M. Johnson, Shan Ping Yu

Research output: Contribution to journalArticlepeer-review

Abstract

We investigated the neuroprotective properties of two M-type K+ channel blockers, linopirdine and its analog XE991, in rat sympathetic neurons deprived of nerve growth factor (NGF). Linopirdine and XE991 promoted sympathetic neuronal survival 48-72 hr after NGF withdrawal in a concentration-dependent manner. Both drugs prevented neuronal apoptosis by blocking the pathway leading to the release of cytochrome c and development of "competence-to-die" after NGF deprivation. Fura-2 Ca2+ imaging showed no significant difference in intracellular free Ca2+ ([Ca2+]i) in the presence or absence of NGF; linopirdine and XE991, on the other hand, caused membrane depolarization and increases in [Ca2+]i. Whole-cell recordings showed that linopirdine and XE991 selectively blocked the M current at neuroprotective concentrations, although they additionally inhibited other K+ currents at high concentrations. Membrane depolarization and [ca2+]i increases induced by linopirdine and XE991 were blocked by the Na+ channel blocker tetrodotoxin (TTX) or by the L-type Ca2+ channel antagonist nifedipine. TTX and nifedipine also prevented the neuroprotection elicited by linopirdine or XE991. We propose that Na + channel activation amplifies the membrane depolarization produced by M channel blockade and is essential for subsequent Ca2+ entry via the L-type Ca2+ channel. The interaction of these three classes of ion channels highlights an integrated anti-apoptosis mechanism in sympathetic neurons.

Original languageEnglish (US)
Pages (from-to)114-122
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

Keywords

  • Apoptosis
  • Calcium
  • Cortical neuron
  • Linopirdine
  • M-type potassium channel
  • Nerve growth factor
  • Sympathetic neuron
  • Tetrodotoxin
  • XE991

ASJC Scopus subject areas

  • Neuroscience(all)

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