title: Role of voltage-gated Ca2+ channels and intracellular Ca2+ in rat sympathetic neuron survival and function promoted by high K+ and cyclic AMP in the presence or absence of NGF.
abstract: We have examined how NGF-dependent rat sympathetic neurons maintain Ca2+ homeostasis when challenged with high K+ or 8-(4-chlorophenylthio)cyclic AMP (CPTcAMP), two survival factors. In the presence of NGF, high K+ (55 mM) caused a stable, 65% reduction in the density of cell soma voltage-sensitive Ca2+ channels within 2 days. Although resting [Ca2+]i was elevated by 1.6-fold, this was 50% less than the rise in [Ca2+]i measured before down-regulation occurred, suggesting that down-regulation may help prevent the toxic effects of persistently elevated [Ca2+]i. Inhibition of protein synthesis by cycloheximide blocked recovery from down-regulation. Moreover, treatment with cycloheximide or actinomycin-D caused a 2-fold rise in the peak Ca2+ current, suggesting that voltage-sensitive Ca2+ channel activity may be tonically attenuated during normal growth. In the absence of NGF, neurons survived for several days in high K+ medium with no significant rise in resting [Ca2+]i, although neurites did not grow. Neither Ca2+ channel density nor resting [Ca2+]i were altered in neurons surviving with CPTcAMP. Moreover, CPTcAMP lowered the dependence on extracellular Ca2+. However, the dihydropyridine antagonist nitrendipine blocked both high K(+)- and CPTcAMP-dependent survival although it had no effect in the presence of NGF. Thus, in the absence of NGF, sympathetic neurons do not require elevation of [Ca2+]i above resting levels to survive with either high K+ or CPTcAMP, but dihydropyridine-sensitive Ca2+ channel activity may be essential for their survival promoting actions.
authors.affiliation: Department of Human Anatomy, University of Oxford, UK.
authors.forename: R D
authors.initials: RD
authors.lastname: Murrell
authors.forename: A M
authors.initials: AM
authors.lastname: Tolkovsky
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D009414:Nerve Growth Factors; D013873:Thionucleotides; D003609:Dactinomycin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D003513:Cycloheximide; D000242:Cyclic AMP; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine