TY - JOUR
T1 - β-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic β cells
AU - Sonoda, Noriyuki
AU - Imamura, Takeshi
AU - Yoshizaki, Takeshi
AU - Babendure, Jennie L.
AU - Lu, Juu Chin
AU - Olefsky, Jerrold M.
PY - 2008/5/6
Y1 - 2008/5/6
N2 - Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from enteroendocrine L cells and potentiates glucose-dependent insulin secretion in pancreatic β cells. Recently the GLP-1 receptor (GLP-1 R) has been a focus for new anti-diabetic therapy with the introduction of GLP-1 analogues and DPP-IV inhibitors, and this has stimulated additional interest in the mechanisms of GLP-1 signaling. Here we identify a mechanism for GLP-1 action, showing that the scaffold protein β-arrestin-1 mediates the effects of GLP-1 to stimulate cAMP production and insulin secretion in β cells. Using a coimmunoprecipitation technique, we also found a physical association between the GLP-1 R and β-arrestin-1 in cultured INS-1 pancreatic β cells. β-Arrestin-1 knockdown broadly attenuated GLP-1 signaling, causing decreased ERK and CREB activation and IRS-2 expression as well as reduced cAMP levels and impaired insulin secretion. However, β-arrestin-1 knockdown did not affect GLP-1 R surface expression and ligand-induced GLP-1 R internalization/desensitization. Taken together, these studies indicate that β-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action.
AB - Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted from enteroendocrine L cells and potentiates glucose-dependent insulin secretion in pancreatic β cells. Recently the GLP-1 receptor (GLP-1 R) has been a focus for new anti-diabetic therapy with the introduction of GLP-1 analogues and DPP-IV inhibitors, and this has stimulated additional interest in the mechanisms of GLP-1 signaling. Here we identify a mechanism for GLP-1 action, showing that the scaffold protein β-arrestin-1 mediates the effects of GLP-1 to stimulate cAMP production and insulin secretion in β cells. Using a coimmunoprecipitation technique, we also found a physical association between the GLP-1 R and β-arrestin-1 in cultured INS-1 pancreatic β cells. β-Arrestin-1 knockdown broadly attenuated GLP-1 signaling, causing decreased ERK and CREB activation and IRS-2 expression as well as reduced cAMP levels and impaired insulin secretion. However, β-arrestin-1 knockdown did not affect GLP-1 R surface expression and ligand-induced GLP-1 R internalization/desensitization. Taken together, these studies indicate that β-arrestin-1 plays a role in GLP-1 signaling leading to insulin secretion, defining a previously undescribed mechanism for GLP-1 action.
KW - CREB
KW - IRS-2
UR - http://www.scopus.com/inward/record.url?scp=44349129654&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44349129654&partnerID=8YFLogxK
U2 - 10.1073/pnas.0710402105
DO - 10.1073/pnas.0710402105
M3 - Article
C2 - 18445652
AN - SCOPUS:44349129654
SN - 0027-8424
VL - 105
SP - 6614
EP - 6619
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -