The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs.
Epac2, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rap1, is activated by adenosine 3',5'-monophosphate. Fluorescence resonance energy transfer and binding experiments revealed that sulfonylureas, widely used antidiabetic drugs, interact directly with Epac2. Sulfonylureas activated Rap1 specifically through Epac2. Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, and the glucose-lowering effect of the sulfonylurea tolbutamide was decreased in these mice. Epac2 thus contributes to the effect of sulfonylureas to promote insulin secretion. Because Epac2 is also required for the action of incretins, gut hormones crucial for potentiating insulin secretion, it may be a promising target for antidiabetic drug development.
Zhang
Chang-Liang
CL
Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Katoh
Megumi
M
Shibasaki
Tadao
T
Minami
Kohtaro
K
Sunaga
Yasuhiro
Y
Takahashi
Harumi
H
Yokoi
Norihide
N
Iwasaki
Masahiro
M
Miki
Takashi
T
Seino
Susumu
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D005947:Glucose / Q000008:administration & dosage; D005905:Glyburide / Q000378:metabolism / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014044:Tolbutamide / Q000378:metabolism / Q000494:pharmacology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D001786:Blood Glucose; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D007004:Hypoglycemic Agents; D007328:Insulin; C486707:Rapgef4 protein, mouse; D013453:Sulfonylurea Compounds; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014044:Tolbutamide; D000242:Cyclic AMP; D020827:rap1 GTP-Binding Proteins; D005947:Glucose; D005905:Glyburide