Possible Involvement of Transient Receptor Potential Channels in Electrophile-Induced Insulin Secretion from RINm5F Cells
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Endogenously produced reactive oxygen species reportedly stimulate insulin secretion from islet β-cells. However, the molecular machinery that governs the oxidant-induced insulin secretion has yet to be determined. The present study demonstrates, using rat islet β-cell-derived RINm5F cells, the involvement of the transient receptor potential (TRP) cation channels in the insulin secretion induced by the lipid peroxidation product 4-hydroxy-2-nonenal. Short-term (1 h) exposure of 4-hydroxy-2-nonenal induced a transient increase in intracellular Ca<sup>2+</sup> concentration and subsequent insulin secretion in a concentration-dependent manner. The increase in intracellular Ca<sup>2+</sup> concentration seemed to be due to an influx through the L-type voltage-dependent Ca<sup>2+</sup> channel, since it was not observed when extracellular Ca<sup>2+</sup> was absent and was inhibited almost completely by diltiazem or nifedipine. Ruthenium red, a non-specific inhibitor of TRP channels, inhibited the Ca<sup>2+</sup> influx and insulin secretion evoked by 4-hydroxy-2-nonenal. Among the TRP channels, TRPA1 was found to be predominantly expressed, not only in RINm5F cells, but also rat islets. TRPA1 agonists, allylisothiocyanate and 15-deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>, significantly induced Ca<sup>2+</sup> influx, and a specific inhibitor TRPA1, HC-030031, blocked the effects elicited by 4-hydroxy-2-nonenal. These results suggest that 4-hydroxy-2-nonenal induces Ca<sup>2+</sup> influx <i>via</i> the activation of TRP channels, including TRPA1, which appears to be coupled with the L-type voltage-dependent Ca<sup>2+</sup> channel, and ultimately insulin secretion in RINm5F cells.
- Biological and Pharmaceutical Bulletin
Biological and Pharmaceutical Bulletin 35(3), 346-354, 2012
The Pharmaceutical Society of Japan