Modulation of L-type calcium channels by human IgM anti-GM1 antibodies

Increased titers of IgM anti-GM1 antibodies are present in some patients with lower motor neuron disease (LMND) or motor neuropathy (MN), but their pathogenic role and the mechanism of action are unclear. Using a fluorimetric ap- proach, we have examined the hypothesis that the pentameric IgM anti-GM1 antibodies could alter calcium concentration in N18 neuroblastoma cells. Sera with human IgM anti-GM1 antibodies were obtained from 5 patients with LMND and 2 patients with MN. Direct application of either human IgM anti-GM1 antibodies or the B subunit of CT to N18 neuroblastoma cells induced a sustained influx of manganese ions, as indicated by a quench of the intracellular fura-2 fluorescence. Furthermore, the dihydropyridine L-type channel antagonists completely inhibited the manganese influx, suggesting that it is due to activation of L-type, voltage-dependent calcium channels (VGCC). The magnitude of the influx was correlated with antibody titers. None of the human control sera induced an ion influx, pointing to the selective participation of the pentameric IgM isotype of anti-GM1 in the modulation of L-type calcium channel opening. Given that L-type calcium channels are present on motor neurons, the modulation of these calcium channels by IgM GM1 antisera may have important implications in diseases such as LMND and MN.