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Am J Physiol Cell Physiol ; 316(3): C434-C443, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30649920

ABSTRACT

ß-Cell swelling induces membrane depolarization, which has been suggested to be caused at least partly by the activation of cation channels. Here, we show the identification of the cation channels. In isolated mouse pancreatic ß-cells, the exposure to 30% hypotonic solution elicited an increase in cytosolic Ca2+ concentration ([Ca2+]c). The [Ca2+]c elevation was partially inhibited by ruthenium red, a blocker of several Ca2+-permeable channels including transient receptor potential vanilloid receptors [transient receptor potential cation channel subfamily V (TRPV)], and by nicardipine, but not by the depletion of intracellular Ca2+ stores with thapsigargin and caffeine. The hypotonic stimulation also increased insulin secretion from isolated mouse islets, which was significantly suppressed by ruthenium red. Expression of TRPV2 and TRPV4 was confirmed in mouse pancreatic islets and the MIN6 ß-cell line by RT-PCR, Western blot, and immunohistochemical analyses. However, neither 4α-phorbol 12,13-didecanoate nor GSK1016790A, TRPV4 activators, showed any apparent effect on [Ca2+]c in isolated mouse ß-cells or in MIN6 cells. In contrast, probenecid, a TRPV2 activator, induced an increase in [Ca2+]c in MIN6 cells, which was attenuated by ruthenium red. Moreover, the [Ca2+]c elevation induced by 30% hypotonic stimulation was significantly reduced by knockdown of TRPV2 with siRNA and by tranilast, a TRPV2 inhibitor. The knockdown of TRPV2 also decreased insulin secretion induced by the hypotonic stimulation. In addition, glucose-stimulated insulin secretion was also significantly reduced in the TRPV2-knockdown MIN6 cells. These results suggest that osmotic cell swelling activates TRPV2 in mouse ß-cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels and insulin secretion.


Subject(s)
Calcium Channels/metabolism , Insulin Secretion/physiology , Insulin-Secreting Cells/metabolism , Insulin/metabolism , TRPV Cation Channels/metabolism , Animals , Calcium/metabolism , Calcium Signaling/physiology , Cell Membrane/metabolism , Cells, Cultured , Cytosol/metabolism , Glucose/metabolism , Male , Mice , RNA, Small Interfering/metabolism
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