A selective small molecule glucagon-like peptide-1 secretagogue acting via depolarization-coupled Ca(2+) influx.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates insulin secretion in a glucose-dependent manner. Selective GLP-1 secretagogue would be one of the potential therapeutic targets for type 2 diabetes. Here, we describe a newly identified small molecule compound (compound A) that stimulates secretion of GLP-1 in murine enteroendocrine cell lines, STC-1 and GLUTag cells, and in primary cultured fetal rat intestinal cells (FRIC). The underlying mechanism by which compound A stimulated GLP-1 secretion was also examined. Compound A stimulated GLP-1 secretion from STC-1 cells in a concentration-dependent manner, and also from GLUTag cells and FRIC. The action of compound A was selective against other tested endocrine functions such as secretion of insulin from rat islets, growth hormone from rat pituitary gland cells, and norepinephrine from rat PC-12 cells. In STC-1 cells, the compound A-stimulated GLP-1 secretion was neither due to cyclic AMP production nor to Ca(2+) release from intracellular stores, but to extracellular Ca(2+) influx. The response was inhibited by the presence of either L-type Ca(2+) channel blockers or K(+) ionophore. Perforated-patch clamp study revealed that compound A induces membrane depolarization. These results suggest that neither Galphas- nor Galphaq-coupled signaling account for the mechanism of action, but depolarization-coupled Ca(2+) influx from extracellular space is the primary cause for the GLP-1 secretion stimulated by compound A. Identifying a specific target molecule for compound A will reveal a selective regulatory pathway that leads to depolarization-mediated GLP-1 secretion.
Eiki
Jun-ichi
J
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Tsukuba, Ibaraki, Japan. junichi_eiki@merck.com
Saeki
Kaori
K
Nagano
Norihiro
N
Iino
Tomoharu
T
Yonemoto
Mari
M
Takayenoki-Iino
Yoko
Y
Ito
Satoru
S
Nishimura
Teruyuki
T
Sato
Yoshiyuki
Y
Bamba
Makoto
M
Watanabe
Hitomi
H
Sasaki
Kaori
K
Ohyama
Sumika
S
Kanatani
Akio
A
Nagase
Toshio
T
Yada
Toshihiko
T