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Analyses of Mitochondrial Calcium Influx in Isolated Mitochondria and Cultured Cells
Published on: April 27, 2018
Maitotoxin converts the plasmalemmal Ca(2+) pump into a Ca(2+)-permeable nonselective cation channel
William G Sinkins1, Mark Estacion, Vikram Prasad
1Department of Physiology, Rammelkamp Center for Education and Research, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
American Journal of Physiology. Cell Physiology
|October 2, 2009
Summary
Maitotoxin (MTX) transforms the plasma membrane Ca(2+)-ATPase (PMCA) pump into a calcium-permeable cation channel. This study identifies the PMCA as the molecular target of MTX, explaining its cellular effects.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Maitotoxin (MTX) is known to activate Ca(2+)-permeable nonselective cation channels, leading to increased intracellular calcium.
- The molecular identity of these MTX-activated channels has remained elusive.
- Palytoxin (PTX), a related marine toxin, activates the Na(+)-K(+)-ATPase (NKA) pump, converting it into a cation channel.
Purpose of the Study:
- To investigate the hypothesis that MTX binds to the plasma membrane Ca(2+)-ATPase (PMCA) pump.
- To determine if MTX converts the PMCA into a Ca(2+)-permeable nonselective cation channel.
Main Methods:
- Overexpression of PMCA in Spodoptera frugiperda (Sf9) and human embryonic kidney (HEK) 293 cells.
- Measurement of MTX-induced whole-cell membrane currents.
- Assessment of MTX effects in wild-type and PMCA-overexpressing cells, including sensitivity to pump ligands (Ca(2+), ATP).
- PMCA1 knockdown using small interfering RNA (siRNA) and analysis in genetically modified mouse embryonic fibroblasts (PMCA1(+/-) PMCA4(-/-)).
- Inhibition assays of PMCA catalytic activity by MTX.
Main Results:
- Enhanced PMCA expression significantly increased MTX-induced whole-cell currents in both Sf9 and HEK 293 cells.
- MTX-induced currents were sensitive to Ca(2+) and ATP, consistent with PMCA activity.
- PMCA1 knockdown or genetic deficiency reduced MTX-induced currents.
- MTX inhibited PMCA catalytic activity (Ca(2+)-ATPase activity).
Conclusions:
- MTX binds to the PMCA pump.
- MTX converts the PMCA into a Ca(2+)-permeable nonselective cation channel.
- This finding elucidates the molecular mechanism of MTX-induced cellular calcium influx.
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