Role of GPR40 in fatty acid action on the beta cell line INS-1E.
GPR40 is a G protein-coupled receptor expressed preferentially in beta cells, that has been implicated in mediating free fatty acid-stimulated insulin release. GPR40 RNAi impaired the ability of palmitic acid (PA) to increase both insulin secretion and intracellular calcium ([Ca2+]i). The PA-dependent [Ca2+]i increase was attenuated by inhibitors of Galphaq, PLC, and SERCA. Thus GPR40 activates the Galphaq pathway, leading to release of Ca2+ from the ER. Yet the GPR40-dependent [Ca2+]i rise was dependent on extracellular Ca2+ and elevated glucose, and was blocked by inhibition of L-type calcium channels (LTCC) or opening of the K(ATP) channel; this suggests that GPR40 promotes Ca2+ influx through up-regulation of LTCC pre-activated by glucose and membrane depolarization. Taken together, the data indicate that GPR40 mediates the increase in [Ca2+]i and insulin secretion through the Galphaq-PLC pathway, resulting in release of Ca2+ from the ER and leading to up-regulation of Ca2+ influx via LTCC.
Shapiro
Hagit
H
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Shachar
Sigal
S
Sekler
Israel
I
Hershfinkel
Michal
M
Walker
Michael D
MD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D015640:Ion Channel Gating / Q000187:drug effects; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism* / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D020746:Calcium Channels, L-Type; C473035:G-protein-coupled receptor 40, rat; D007328:Insulin; D015221:Potassium Channels; D043562:Receptors, G-Protein-Coupled; D019308:Palmitic Acid; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005947:Glucose; D002118:Calcium