Multiparameter screening reveals a role for Na+ channels in cytokine-induced β-cell death.
Pancreatic β-cell death plays a role in both type 1 and type 2 diabetes, but clinical treatments that specifically target β-cell survival have not yet been developed. We have recently developed live-cell imaging-based, high-throughput screening methods capable of identifying factors that modulate pancreatic β-cell death, with the hope of finding drugs that can intervene in this process. In the present study, we used a high-content screen and the Prestwick Chemical Library of small molecules to identify drugs that block cell death resulting from exposure to a cocktail of cytotoxic cytokines (25 ng/mL TNF-α, 10 ng/mL IL-1β, and 10 ng/mL IFN-γ). Data analysis with self-organizing maps revealed that 19 drugs had profiles similar to that of the no cytokine condition, indicating protection. Carbamazepine, an antiepileptic Na(+) channel inhibitor, was particularly interesting because Na(+) channels are not generally considered targets for antiapoptotic therapy in diabetes and because the function of these channels in β-cells has not been well studied. We analyzed the expression and characteristics of Na(+) currents in mature β-cells from MIP-GFP mice. We confirmed the dose-dependent protective effects of carbamazepine and another use-dependent Na(+) channel blocker in cytokine-treated mouse islet cells. Carbamazepine down-regulated the proapoptotic and endoplasmic reticulum stress signaling induced by cytokines. Together, these studies point to Na(+) channels as a novel therapeutic target in diabetes.
Department of Cellular and Physiological Sciences (Y.H.C.Y., J.D.J.), Department of Anesthesiology, Pharmacology, and Therapeutics (Y.Y.V., H.T.K.), and Department of Biochemistry and Molecular Biology (M.R.), University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Yu Hsuan Carol
YH
Yang
Yury Y
YY
Vilin
Michel
M
Roberge
Harley T
HT
Kurata
James D
JD
Johnson
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002220:Carbamazepine / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D057166:High-Throughput Screening Assays; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D016207:Cytokines; D007328:Insulin; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; D002220:Carbamazepine; D002118:Calcium