QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Xia, S. Articles by Yu, S. P. Search for Related Content PubMed PubMed Citation Articles by Xia, S. Articles by Yu, S. P.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				F. Schuetz, S. Kumar, P. Poronnik, and D. J. Adams Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1 Am J Physiol Cell Physiol, July 1, 2008; 295(1): C73 - C80. [Abstract] [Full Text] [PDF]

				D. L. Prole, P. A. Lima, and N. V. Marrion Mechanisms Underlying Modulation of Neuronal KCNQ2/KCNQ3 Potassium Channels by Extracellular Protons J. Gen. Physiol., November 24, 2003; 122(6): 775 - 793. [Abstract] [Full Text] [PDF]

				P. Tosetti, V. Parente, V. Taglietti, K. Dunlap, and M. Toselli Chick RGS2L demonstrates concentration-dependent selectivity for pertussis toxin-sensitive and -insensitive pathways that inhibit L-type Ca2+ channels J. Physiol., May 15, 2003; 549(1): 157 - 169. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help