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Volume 22
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Article

TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase

by
Loretta Ferrera
1,2,
Raffaella Barbieri
1,
Cristiana Picco
1,
Paolo Zuccolini
1,
Alessia Remigante
1,3,
Sara Bertelli
1,
Maria Rita Fumagalli
1,4,
Giovanni Zifarelli
1,
Caterina A. M. La Porta
1,4,
Paola Gavazzo
1 and
Michael Pusch
1,*
1
Biophysics Institute, National Research Council, 16149 Genova, Italy
2
U.O.C. Genetica Medica, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, 16147 Genoa, Italy
3
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy
4
Center for Complexity and Biosystems, Department of Environmental Science and Policy, University of Milan, 20133 Milano, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(16), 8359; https://doi.org/10.3390/ijms22168359
Submission received: 28 June 2021 / Revised: 29 July 2021 / Accepted: 2 August 2021 / Published: 4 August 2021
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Oxidative Stress-Related Diseases)
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Abstract

Tumor microenvironments are often characterized by an increase in oxidative stress levels. We studied the response to oxidative stimulation in human primary (IGR39) or metastatic (IGR37) cell lines obtained from the same patient, performing patch-clamp recordings, intracellular calcium ([Ca2+]i) imaging, and RT-qPCR gene expression analysis. In IGR39 cells, chloramine-T (Chl-T) activated large K+ currents (KROS) that were partially sensitive to tetraethylammonium (TEA). A large fraction of KROS was inhibited by paxilline—a specific inhibitor of large-conductance Ca2+-activated BK channels. The TEA-insensitive component was inhibited by senicapoc—a specific inhibitor of the Ca2+-activated KCa3.1 channel. Both BK and KCa3.1 activation were mediated by an increase in [Ca2+]i induced by Chl-T. Both KROS and [Ca2+]i increase were inhibited by ACA and clotrimazole—two different inhibitors of the calcium-permeable TRPM2 channel. Surprisingly, IGR37 cells did not exhibit current increase upon the application of Chl-T. Expression analysis confirmed that the genes encoding BK, KCa3.1, and TRPM2 are much more expressed in IGR39 than in IGR37. The potassium currents and [Ca2+]i increase observed in response to the oxidizing agent strongly suggest that these three molecular entities play a major role in the progression of melanoma. Pharmacological targeting of either of these ion channels could be a new strategy to reduce the metastatic potential of melanoma cells, and could complement classical radio- or chemotherapeutic treatments.
Keywords: melanoma; oxidative stress; potassium channels; intracellular calcium; TRP channels melanoma; oxidative stress; potassium channels; intracellular calcium; TRP channels

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MDPI and ACS Style

Ferrera, L.; Barbieri, R.; Picco, C.; Zuccolini, P.; Remigante, A.; Bertelli, S.; Fumagalli, M.R.; Zifarelli, G.; La Porta, C.A.M.; Gavazzo, P.; et al. TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase. Int. J. Mol. Sci. 2021, 22, 8359. https://doi.org/10.3390/ijms22168359

AMA Style

Ferrera L, Barbieri R, Picco C, Zuccolini P, Remigante A, Bertelli S, Fumagalli MR, Zifarelli G, La Porta CAM, Gavazzo P, et al. TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase. International Journal of Molecular Sciences. 2021; 22(16):8359. https://doi.org/10.3390/ijms22168359

Chicago/Turabian Style

Ferrera, Loretta, Raffaella Barbieri, Cristiana Picco, Paolo Zuccolini, Alessia Remigante, Sara Bertelli, Maria Rita Fumagalli, Giovanni Zifarelli, Caterina A. M. La Porta, Paola Gavazzo, and et al. 2021. "TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase" International Journal of Molecular Sciences 22, no. 16: 8359. https://doi.org/10.3390/ijms22168359

APA Style

Ferrera, L., Barbieri, R., Picco, C., Zuccolini, P., Remigante, A., Bertelli, S., Fumagalli, M. R., Zifarelli, G., La Porta, C. A. M., Gavazzo, P., & Pusch, M. (2021). TRPM2 Oxidation Activates Two Distinct Potassium Channels in Melanoma Cells through Intracellular Calcium Increase. International Journal of Molecular Sciences, 22(16), 8359. https://doi.org/10.3390/ijms22168359

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