Involvement of cAMP/EPAC/TRPM2 activation in glucose- and incretin-induced insulin secretion.
In pancreatic β-cells, closure of the ATP-sensitive K(+) (K(ATP)) channel is an initial process triggering glucose-stimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K(ATP) channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose- and incretin-activated NSCC (TRPM2) works in concert with closure of the KATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in β-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Masashi
M
Yosida
Integrative Physiology, Jichi Medical University, Shimotsuke, Japan.
Katsuya
K
Dezaki
National Institute for Physiological Sciences, Okazaki, Japan.
Kunitoshi
K
Uchida
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Shiho
S
Kodera
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Nien V
NV
Lam
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Kiyonori
K
Ito
Integrative Physiology, Jichi Medical University, Shimotsuke, Japan.
Rauza S
RS
Rita
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Hodaka
H
Yamada
Integrative Physiology, Jichi Medical University, Shimotsuke, Japan.
Kenju
K
Shimomura
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
San-e
SE
Ishikawa
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan.
Hitoshi
H
Sugawara
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan Nerima Hikarigaoka Hospital, Nerima, Japan.
Masanobu
M
Kawakami
National Institute for Physiological Sciences, Okazaki, Japan.
Makoto
M
Tominaga
Integrative Physiology, Jichi Medical University, Shimotsuke, Japan National Institute for Physiological Sciences, Okazaki, Japan.
Toshihiko
T
Yada
Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan mkakei@jichi.ac.jp.
Masafumi
M
Kakei
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000378:metabolism; D000077270:Exenatide; D005947:Glucose / Q000494:pharmacology; D054795:Incretins / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D050053:TRPM Cation Channels / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
D054795:Incretins; D007328:Insulin; D010455:Peptides; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D014688:Venoms; D004917:Erythromycin; C057513:erythromycin propionate-N-acetylcysteinate; D000077270:Exenatide; D000242:Cyclic AMP; D005947:Glucose; D002118:Calcium; D000111:Acetylcysteine