TRPM4 impacts on Ca2+ signals during agonist-induced insulin secretion in pancreatic beta-cells.
TRPM4 is a Ca(2+)-activated non-selective cation (CAN) channel that functions in cell depolarization, which is important for Ca(2+) influx and insulin secretion in pancreatic beta-cells. We investigated TRPM4 expression and function in the beta-cell lines HIT-T15 (hamster), RINm5F (rat), beta-TC3 (mouse), MIN-6 (mouse) and the alpha-cell line INR1G9 (hamster). By RT-PCR, we identified TRPM4 transcripts in alpha- and beta-cells. Patch-clamp recordings with increasing Ca(2+) concentrations resulted in a dose-dependent activation of TRPM4 with the greatest depolarizing currents recorded from hamster-derived cells. Further, Ca(2+) imaging experiments revealed that inhibition of TRPM4 by a dominant-negative effect significantly decreased the magnitude of the Ca(2+) signals generated by agonist stimulation compared to control cells. The decrease in the [Ca(2+)](i) resulted in reduced insulin secretion. Our data suggest that depolarizing currents generated by TRPM4 are an important component in the control of intracellular Ca(2+) signals necessary for insulin secretion and perhaps glucagon from alpha-cells.
Marigo
V
V
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
Courville
K
K
Hsu
W H
WH
Feng
J M
JM
Cheng
H
H
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
D007328:Insulin; D050053:TRPM Cation Channels; D011189:Potassium Chloride; D005947:Glucose; D005905:Glyburide; D002118:Calcium