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J. Biol. Chem., Vol. 282, Issue 18, 13410-13418, May 4, 2007

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Somatostatin Receptors Signal through EFA6A-ARF6 to Activate Phospholipase D in Clonal -Cells^*

Justin A. Grodnitzky¹, Nasser Syed¹, Michael J. Kimber, Tim A. Day, Julie G. Donaldson, and Walter H. Hsu²

From the Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011 and the Laboratory of Cell Biology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

Somatostatin (SS) is a peptide hormone that inhibits insulin secretion in -cells by activating its G_i/o-coupled receptors. Our previous work indicated that a -dimer of G_i/o coupled to SS receptors can activate phospholipase D1 (PLD1) (Cheng, H., Grodnitzky, J. A., Yibchok-anun, S., Ding, J., and Hsu, W. H. (2005) Mol. Pharmacol. 67, 2162–2172). The aim of the present study was to elucidate the mechanisms underlying SS-induced PLD activation. We demonstrated the presence of ADP-ribosylation factor Arf1 and Arf6 in clonal -cells, HIT-T15. We also determined that the activation of PLD1 was mediated through Arf6. Overexpression of dominant-negative (dn) Arf6 mutant, Arf6(T27N), and suppression of mRNA levels using siRNA, both abolished SS-induced PLD activation, while overexpression of wild type Arf6 further enhanced this PLD activation. In contrast, overexpression of dn-Arf1 mutant Arf1(T31N) or dn-Arf5 mutant Arf5(T31N) failed to reduce SS-induced PLD activation. These findings suggested that Arf6, but not Arf1 or Arf5, mediates the effect of SS. We further determined the involvement of the Arf6 guanine nucleotide exchange factor (GEF) EFA6A, a GEF previously thought to be found predominantly in the brain, in the activation of PLD1 in HIT-T15 cells. Using Northern and Western blot analyses, both mRNA and protein of EFA6A were found in these cells. Overexpression of dn-EFA6A mutant, EFA6A(E242K), and suppression of mRNA levels using siRNA, both abolished SS-induced PLD activation, whereas overexpression of dn-EFA6B mutant, EFA6B(E651K), failed to reduce SS-induced PLD activation. In addition, overexpression of dn-ARNO mutant, ARNO(E156K), another GEF of Arf6, had no effect on SS-induced activation of PLD. Taken together, these results suggest that SS signals through EFA6A to activate Arf6-PLD cascade.

Received for publication, March 6, 2007

^* 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biomedical Sciences, Iowa Sate University, 2008 Veterinary Medicine, Ames, IA 50011-1250. Tel.: 515-294-6864; Fax: 515-294-2315; E-mail: whsu{at}iastate.edu.

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