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The Journal of Neuroscience, January 1, 2002, 22(1):114-122

Multiple Channel Interactions Explain the Protection of Sympathetic Neurons from Apoptosis Induced by Nerve Growth Factor Deprivation

Shuli Xia^{1, 3}, Patricia A. Lampe², Mohanish Deshmukh², Aizhen Yang^{1, 3}, Barry S. Brown⁴, Steve M. Rothman^{1, 2}, Eugene M. Johnson Jr^{1, 2, 3}, and Shan Ping Yu^{1, 3}

Departments of ¹ Neurology and ² Molecular Biology and Pharmacology and ³ Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁴ DuPont Pharmaceuticals Research Laboratories, General Pharmacology, Wilmington, Delaware 19880

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.

Key words: apoptosis; calcium; M-type potassium channel; nerve growth factor; sympathetic neuron; cortical neuron; tetrodotoxin; linopirdine; XE991

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Copyright © 2002 Society for Neuroscience  0270-6474/02/221114-09$05.00/0

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