title: Multiple channel interactions explain the protection of sympathetic neurons from apoptosis induced by nerve growth factor deprivation.
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.
authors.affiliation: Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Shuli
authors.initials: S
authors.lastname: Xia
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Lampe
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
authors.forename: Aizhen
authors.initials: A
authors.lastname: Yang
authors.forename: Barry S
authors.initials: BS
authors.lastname: Brown
authors.forename: Steve M
authors.initials: SM
authors.lastname: Rothman
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Johnson
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D020932:Nerve Growth Factor / Q000172:deficiency* / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D017783:Superior Cervical Ganglion; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D003574:Cytochrome c Group; D007211:Indoles; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D020932:Nerve Growth Factor; C061017:linopirdine; D002118:Calcium