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J. Biol. Chem., Vol. 281, Issue 39, 28499-28507, September 29, 2006

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Glucagon-like Peptide 1 Activates Protein Kinase C through Ca²⁺-dependent Activation of Phospholipase C in Insulin-secreting Cells^*

Yuko Suzuki, Hui Zhang, Naoaki Saito^¶, Itaru Kojima, Tetsumei Urano, and Hideo Mogami¹

From the Department of Physiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan, the Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan, and the ^¶Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan

Although the stimulatory effect of glucagon-like peptide 1 (GLP-1), a cAMP-generating agonist, on Ca²⁺ signal and insulin secretion is well established, the underlying mechanisms remain to be fully elucidated. We recently discovered that Ca²⁺ influx alone can activate conventional protein kinase C (PKC) as well as novel PKC in insulin-secreting (INS-1) cells. Building on this earlier finding, here we examined whether GLP-1-evoked Ca²⁺ signaling can activate PKC and PKC at a substimulatory concentration of glucose (3 mM) in INS-1 cells. We first showed that GLP-1 translocated endogenous PKC and PKC from the cytosol to the plasma membrane. Next, we assessed the phosphorylation state of the PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS), by using MARCKS-GFP. GLP-1 translocated MARCKS-GFP to the cytosol in a Ca²⁺-dependent manner, and the GLP-1-evoked translocation of MARCKS-GFP was blocked by PKC inhibitors, either a broad PKC inhibitor, bisindolylmaleimide I, or a PKC inhibitor peptide, antennapedia peptide-fused pseudosubstrate PKC-(149–164) (antp-PKC) and a conventional PKC inhibitor, Gö-6976. Furthermore, forskolin-induced translocation of MARCKS-GFP was almost completely inhibited by U73122 [GenBank] , a putative inhibitor of phospholipase C. These observations were verified in two different ways by demonstrating 1) forskolin-induced translocation of the GFP-tagged C1 domain of PKC and 2) translocation of PKC-DsRed and PKC-GFP. In addition, PKC inhibitors reduced forskolin-induced insulin secretion in both INS-1 cells and rat islets. Thus, GLP-1 can activate PKC and PKC, and these GLP-1-activated PKCs may contribute considerably to insulin secretion at a substimulatory concentration of glucose.

Received for publication, May 4, 2006 , and in revised form, July 21, 2006.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Science, Education, Sports, and Culture of Japan and grants from the Takeda Science Foundation and Toukai Foundation for Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. Tel.: 81-53-435-2249; Fax: 81-53-435-7020; E-mail: hmogami{at}hama-med.ac.jp.

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