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J. Biol. Chem., Vol. 283, Issue 1, 166-174, January 4, 2008

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Regulation of Platelet Dense Granule Secretion by the Ral GTPase-Exocyst Pathway^*

Mitsunori Kawato, Ryutaro Shirakawa¹, Hirokazu Kondo, Tomohito Higashi¹, Tomoyuki Ikeda, Katsuya Okawa, Shuya Fukai^¶||, Osamu Nureki^¶, Toru Kita, and Hisanori Horiuchi²

From the Department of Cardiovascular Medicine and Frontier Technology Center, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan, ^¶Department of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan, and ^||Life Science Division, Synchrotron Radiation Research Organization, University of Tokyo, Tokyo, 113-0032, Japan

Non-hydrolyzable GTP analogues, such as guanosine 5'-(β, -imido)triphosphate (GppNHp), induce granule secretion from permeabilized platelets in the absence of increased intracellular Ca²⁺. Here, we show that the GppNHp-induced dense granule secretion from permeabilized platelets occurred concomitantly with the activation of small GTPase Ral. This secretion was inhibited by the addition of GTP-Ral-binding domain (RBD) of Sec5, which is a component of the exocyst complex known to function as a tethering factor at the plasma membrane for vesicles. We generated an antibody against Sec5-RBD, which abolished the interaction between GTP-Ral and the exocyst complex in vitro. The addition of this antibody inhibited the GppNHp-induced secretion. These data indicate that Ral mediates the GppNHp-induced dense granule secretion from permeabilized platelets through interaction with its effector, the exocyst complex. Furthermore, GppNHp enhanced the Ca²⁺ sensitivity of dense granule secretion from permeabilized platelets, and this enhancement was inhibited by Sec5-RBD. In intact platelets, the association between Ral and the exocyst complex was induced by thrombin stimulation with a time course similar to that of dense granule secretion and Ral activation. Taken together, our results suggest that the Ral-exocyst pathway participates in the regulation of platelet dense granule secretion by enhancing the Ca²⁺ sensitivity of the secretion.

Received for publication, June 28, 2007 , and in revised form, September 28, 2007.

^* This work was supported by a research grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This study was also supported in part by grants-in-aid from the Takeda Science Foundation and Mitsubishi Pharma Research Foundation. 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 Recipient of Japan Society for the Promotion of Science (JSPS) Research Fellowship for Young Scientists.

² To whom correspondence should be addressed: Dept. of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan. Tel.: 81-75-751-3778; Fax: 81-75-751-3203; E-mail: horiuchi{at}kuhp.kyoto-u.ac.jp.

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