Enhancement of voltage-gated Ca2+ currents induced by daily stimulation of hippocampal neurons with glutamate

Abstract

The regulation of calcium channel currents (ICa) induced by daily stimulation (1 hr) with 10 microM glutamate was studied in full differentiated hippocampal cells in culture. We report a specific enhancement of the high-voltage-activated current type (HVA ICa) ongoing over days. The density of HVA ICa increased about twofold after the second glutamate session, and this enhancement was still observed after the fifth day of treatment, while low-voltage-activated calcium currents (LVA ICa) remained unchanged. During glutamate application, a transient increase of intracellular calcium (Cai) was observed, followed by a slow decay within 2–3 min, and substantial recovery in about 10 min. Similarly, Cai transients induced by periodic membrane depolarization mimicked the long-term effect of glutamate on ICa. These results demonstrate for the first time an increase of ICa in a time frame of days. Since the effect of glutamate on ICa was prevented by cycloheximide, neosynthesis of channel proteins presumably supports this enhancement.

In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

“…In the initial phase of NMDA-overstimulation as in ischaemic conditions Ca 2ϩ influx depends primarily on NMDA-channels (Bading et al, 1995;Garcia et al, 1994). There are good arguments that secondary Ca 2ϩ currents through activated VDCC are involved in the later stages of NMDA-induced cell damage (Garcia et al, 1994;Lobner & Lipton, 1993).…”

“…There are good arguments that secondary Ca 2ϩ currents through activated VDCC are involved in the later stages of NMDA-induced cell damage (Garcia et al, 1994;Lobner & Lipton, 1993). Several mechanisms may underlie increase of Ca 2ϩ currents through VDCCs after overstimulation by NMDA.…”

“…Firstly, membrane depolarization caused by NMDA-channel activation can trigger additional Ca 2ϩ influx through neighbouring VDCCs (Skeen et al,1993). Intracellular messenger systems, including cAMP associated pathways, are thought to be involved in the delayed longterm enhancement of voltage-gated Ca 2ϩ currents after NMDA-receptor stimulation (Chetkovich et al, 1991;Garcia et al, 1994;Mironov & Lux, 1992).…”

“…Massive entry through various channels of Ca 2ϩ into neurons is considered to be the final common pathway leading to irreversible neuronal damage, since persistent high levels of cytosolic free Ca 2ϩ may evoke dysregulations of Ca 2ϩ activated processes which are detrimental to neurons (Clapham, 1995). Both N-methyl-D-aspartate (NMDA) receptoroperated ion channels and voltage-dependent Ca 2ϩ channels (VDCCs) appear to be largely responsible for the massive Ca 2ϩ influx during excitotoxic insults (Garcia et al, 1994;Hartley et al, 1993;Lobner & Lipton, 1993;Rothman & Olney, 1995). During the initial phase of ischaemia Ca 2ϩ influx is shown to be mediated primarily by stimulated NMDA-channels followed by a secondary influx involving other Ca 2ϩ channels (Lobner & Lipton, 1993) activated by voltage changes or intracellular messenger systems (Chetkovich et al, 1991;Garcia et al, 1994;Skeen et al, 1994).…”

“…Both N-methyl-D-aspartate (NMDA) receptoroperated ion channels and voltage-dependent Ca 2ϩ channels (VDCCs) appear to be largely responsible for the massive Ca 2ϩ influx during excitotoxic insults (Garcia et al, 1994;Hartley et al, 1993;Lobner & Lipton, 1993;Rothman & Olney, 1995). During the initial phase of ischaemia Ca 2ϩ influx is shown to be mediated primarily by stimulated NMDA-channels followed by a secondary influx involving other Ca 2ϩ channels (Lobner & Lipton, 1993) activated by voltage changes or intracellular messenger systems (Chetkovich et al, 1991;Garcia et al, 1994;Skeen et al, 1994). Agents that block the Ca 2+ entry through activated NMDA-channels have been demonstrated in several ischaemia model studies to decrease neuronal damage Meldrum & Garthwaite, 1990;Siesjö et al, 1992).…”