Sustained increase in intracellular calcium promotes neuronal survival

Abstract

Ciliary ganglion neurons, half of which normally suffer developmental death in the embryo, will survive in culture in medium supplemented with depolarizing concentrations of potassium. It is not known how elevated potassium acts inside the cell to promote survival. We report here that depolarizing concentrations of extracellular potassium promote neuronal survival by causing a sustained increase in intracellular calcium. Raising extracellular potassium from 5 to 40 mM, an optimal concentration for survival, caused a sustained increase in intracellular calcium from 250 nM to greater than 600 nM. By 26 hr, at which time greater than 90% of neurons in 5 mM potassium had died, the calcium concentration of neurons in 40 mM potassium was still above 400 nM. Reduction of extracellular potassium from 40 to 5 nM, which prevents the increase in survival, also reduced intracellular calcium back to rest levels. PN200-110, a dihydropyridine calcium channel blocker that inhibits the survival-promoting effect of elevated potassium, also prevented and reversed the potassium,-mediated increase in intracellular calcium. In addition, there was a strong, quantitative correlation between the percentage of neuronal survival and the intracellular calcium concentration over a wide range of extracellular potassium concentrations. These results suggest that elevated potassium opens dihydropyridine-sensitive calcium channels, causing a sustained increase in intracellular calcium that quantitatively determines the number of surviving neurons.

Trophic Support of Cultured Spiral Ganglion Neurons by Depolarization Exceeds and Is Additive with that by Neurotrophins or cAMP and Requires Elevation of [Ca2+]iwithin a Set Range

“…Ca 2ϩ influx through L-type channels is specifically required for the trophic effect of depolarization on SGNs, as has been shown previously for several types of neurons (Gallo et al, 1987;Collins and Lile, 1989;Koike et al, 1989;Collins et al, 1991 These results are comparable with those reported previously for sympathetic neurons (Koike et al, 1989;Koike and Tanaka, 1991), although maximal SGN survival appears to occur at a slightly lower [Ca 2ϩ ] i than does maximal sympathetic neuronal survival (Franklin et al, 1995). Most important, our data are consistent with the "calcium homeostasis" or "setpoint" hypothesis for neuronal survival proposed by these authors (Koike et al, 1989;Koike and Tanaka, 1991), which is comparable with one proposed earlier for growth cone stability (Kater et al, 1988 (Choi, 1988;Siesjo et al, 1989).…”

“…Although the calcium homeostasis hypothesis can successfully account for the survival or death of neurons in various depolarizing conditions or after exposure to excitatory amino acids (Collins et al, 1991;Koike and Tanaka, 1991;Franklin and Johnson, 1992), Franklin et al (1995) ] i are potential mediators of the trophic effect of depolarization. The robust trophic response of SGNs to depolarization in vitro suggests that they will of value in investigation of these mechanisms.…”

“…The neurotrophic effect of depolarization is apparently a consequence of a sustained rise in cytosolic Ca 2ϩ , entering through L-type Ca 2ϩ channels (Gallo et al, 1987;Collins and Lile, 1989;Koike et al, 1989;Collins et al, 1991). This is in spite of the critical role of cytosolic Ca 2ϩ in mediating neuronal degeneration (Choi, 1988;Siesjo et al, 1989).…”

“…This is in spite of the critical role of cytosolic Ca 2ϩ in mediating neuronal degeneration (Choi, 1988;Siesjo et al, 1989). A hypothesis unifying these observations proposes that [Ca 2ϩ ] i must rise to a particular "setpoint" to promote survival in the absence of neurotrophic factor; degeneration is the result of very high [Ca 2ϩ ] i (Collins et al, 1991;Koike and Tanaka, 1991;Franklin and Johnson, 1992). Thus, survival occurs within a range of elevated [Ca 2ϩ ] i , with the lower end of the range determined by the Ca 2ϩ setpoint for that neuron and the upper end by that neuron's sensitivity to Ca 2ϩ -mediated neurotoxicity.…”

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).…”