Amyotrophic lateral sclerosis immunoglobulins increase intracellular calcium in a motoneuron cell line.
A hybrid motoneuron cell line (VSC4.1) was used as a model system to study the relationship between alterations in intracellular calcium and subsequent cell death induced by immunoglobulin fractions purified from sera of patients with ALS. Using fluo-3 fluorescence imaging, immunoglobulins from 8 of 10 patients with ALS were found to induce transient increases in intracellular calcium ([Ca2+]i) in differentiated VSC4.1 cells. These transient [Ca2+]i increases required extracellular calcium entry through voltage-gated calcium channels sensitive to synthetic FTX and to high concentrations (>1 microM) of omega-agatoxin IVa. The incidence of transient [Ca2+]i increases induced by ALS immunoglobulins correlated with the extent of cytotoxicity induced by the same ALS immunoglobulins in parallel cultures of VSC4.1 cells. Furthermore, manipulations which blocked transient [Ca2+]i increases (addition of synthetic FTX or omega-agatoxin IVa) also inhibited the cytotoxic effects of ALS immunoglobulins. No transient calcium increases were observed in VSC4.1 cells following addition of immunoglobulins from 7 neurologic disease control patients. However, transient [Ca2+]i increases were observed following addition of immunoglobulins from 4 of 5 patients with myasthenia gravis (MG). The [Ca2+]i changes induced by MG immunoglobulins were not blocked by s-FTX, suggesting that they result from a different mechanism than those induced by ALS immunoglobulins. These results suggest that immunoglobulins from patients with ALS can induce transient increases in intracellular calcium in a motoneuron cell line, which may represent early events in the cascade of processes leading to injury and death of susceptible cells.
Colom
L V
LV
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Alexianu
M E
ME
Mosier
D R
DR
Smith
R G
RG
Appel
S H
SH
D000690:Amyotrophic Lateral Sclerosis / Q000097:blood*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D007136:Immunoglobulins / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D009157:Myasthenia Gravis / Q000097:blood; D051381:Rats
D007136:Immunoglobulins; D002118:Calcium