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.

Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration

“…However, as noted by Yu and colleagues in a landmark paper [37], these studies do not rule out the possibility that reducing K + efflux inhibits apoptosis and promotes neuronal survival. In fact, increases in intracellular Ca 2+ can promote neuronal apoptosis [79, 80], and heightened Ca 2+ levels are not always required for high extracellular K + -facilitated survival of NGF-deprived sympathetic neurons [81]. Importantly, in cortical neurons, Ca 2+ channel blockers do not eliminate neuroprotection by high extracellular K + or tetraethylammonium (TEA, a blocker of delayed rectifying Kv channels) in response to serum deprivation, NMDA, Aβ peptide, or ceramide [37, 56, 57, 60].…”

The role of voltage-gated Ca 2+ channels in neurite growth of cultured chromaffin cells induced by extremely low frequency (ELF) magnetic field stimulation

“…In dorsal root ganglia neurons, NGF has been shown to induce the release of intracellular calcium, independent of extracellular calcium concentrations, suggesting that NGF can mobilize intracellular calcium stores (Yamashita and Kawana 1991). The importance of intracellular Ca 2+ is further shown in sympathetic neurons, which, in the presence of high K + or cAMP, but in the absence of NGF, require dihydropyridine-sensitive Ca 2+ channel activity in order to maintain the basal level of intracellular Ca 2+ necessary for survival (Murell and Tolkovsky 1993).…”

Calmodulin Mediates Brain-derived Neurotrophic Factor Cell Survival Signaling Upstream of Akt Kinase in Embryonic Neocortical Neurons

“…Calcium is a second messenger that mediates a variety of physiological responses of neurons to neurotransmitters and neurotrophic factors, including cell survival responses (14,(21)(22)(23)(24)(25)(26)). An increase in cytoplasmic calcium levels can activate Ras, resulting in the activation of Raf, MEK, and MAPKs (27,28); and calcium can also activate the PI3K-Akt pathway (14).…”