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J. Biol. Chem., Vol. 279, Issue 11, 10730-10737, March 12, 2004

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Munc13-4 Is a GTP-Rab27-binding Protein Regulating Dense Core Granule Secretion in Platelets^*

Ryutaro Shirakawa, Tomohito Higashi, Arata Tabuchi, Akira Yoshioka**, Hiroaki Nishioka, Mitsunori Fukuda, Toru Kita¶, and Hisanori Horiuchi||

From the Departments of Geriatric Medicine and ^¶Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan and the Fukuda Initiative Research Unit, RIKEN, Wako, Saitama 351-0198 Japan

Platelets store self-agonists such as ADP and serotonin in dense core granules. Although exocytosis of these granules is crucial for hemostasis and thrombosis, the underlying mechanism is not fully understood. Here, we show that incubation of permeabilized platelets with unprenylated active mutant Rab27A-Q78L, wild type Rab27A, and Rab27B inhibited the secretion, whereas inactive mutant Rab27A-T23N and other GTPases had no effects. Furthermore, we affinity-purified a GTP-Rab27A-binding protein in platelets and identified it as Munc13-4, a homologue of Munc13-1 known as a priming factor for neurotransmitter release. Recombinant Munc13-4 directly bound to GTP-Rab27A and -Rab27B in vitro, but not other GTPases, and enhanced secretion in an in vitro assay. The inhibition of secretion by unprenylated Rab27A was rescued by the addition of Munc13-4, suggesting that Munc13-4 mediates the function of GTP-Rab27. Thus, Rab27 regulates the dense core granule secretion in platelets by employing its binding protein, Munc13-4.

Received for publication, August 25, 2003 , and in revised form, December 16, 2003.

^* This work was supported by Ministry of Education, Culture, Sports, Science, and Technology Research Grants 11680629 and 15081101 (to H. H.) and 12CE2006, 09281104, and 13307034 (to T. K.), by Health and Labour Sciences Research Grant H14-Tyouju-012 from the Ministry of Health Labour and Welfare (to T. K. and H. H.), and in part by grants from the Takeda Science Foundation, Suzuken Memorial Foundation, the Study Group of Molecular Cardiology, and the Novartis Foundation for Gerontrogical Research (to H. H.). 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.

^** Present address: Department of Internal Medicine, Mitsubishi Kyoto Hospital, Kyoto, 615-8087 Japan.

Present address: Sir William Dunn School of Pathology, University of Oxford, South Parks Rd., Oxford OX1 3RE, United Kingdom.

^|| To whom correspondence should be addressed. Tel.: 81-75-751-3464; Fax: 81-75-751-3574; E-mail: horiuchi{at}kuhp.kyoto-u.ac.jp.

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