ROLE OF VOLTAGE-GATED CA2-AMP IN THE PRESENCE OR ABSENCE OF NGF( CHANNELS AND INTRACELLULAR CA2+ IN RAT SYMPATHETIC NEURON SURVIVAL AND FUNCTION PROMOTED BY HIGH K+ AND CYCLIC)
Rd. Murrell et Am. Tolkovsky, ROLE OF VOLTAGE-GATED CA2-AMP IN THE PRESENCE OR ABSENCE OF NGF( CHANNELS AND INTRACELLULAR CA2+ IN RAT SYMPATHETIC NEURON SURVIVAL AND FUNCTION PROMOTED BY HIGH K+ AND CYCLIC), European journal of neuroscience, 5(10), 1993, pp. 1261-1272
We have examined how NGF-dependent rat sympathetic neurons maintain Ca
2+ homeostasis when challenged with high K+ or 8-(4-chlorophenylthio)c
yclic AMP (CPTcAMP), two survival factors. In the presence of NGF, hig
h K+ (55 mM) caused a stable, 65% reduction in the density of cell som
a 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-regu
lation may help prevent the toxic effects of persistently elevated [Ca
2+]i. Inhibition of protein synthesis by cycloheximide blocked recover
y from down-regulation. Moreover, treatment with cycloheximide or acti
nomycin-D caused a 2-fold rise in the peak Ca2+ current, suggesting th
at voltage-sensitive Ca2+ channel activity may be tonically attenuated
during normal growth. In the absence of NGF, neurons survived for sev
eral days in high K+ medium with no significant rise in resting (Ca2+]
i, although neurites did not grow. Neither Ca2+ channel density nor re
sting [Ca2+]i were altered in neurons surviving with CPTcAMP. Moreover
, CPTcAMP lowered the dependence on extracellular Ca2+. However, the d
ihydropyridine antagonist nitrendipine blocked both high K+- and CPTcA
MP-dependent survival although it had no effect in the presence of NGF
. Thus, in the absence of NGF, sympathetic neurons do not require elev
ation of [Ca2+]i above resting levels to survive with either high K+ o
r CPTcAMP, but dihydropyridine-sensitive Ca2+ channel activity may be
essential for their survival promoting actions.