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The Journal of Neuroscience, January 3, 2007, 27(1):190-202; doi:10.1523/JNEUROSCI.2537-06.2007

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Cellular/Molecular
RalA and RalB Function as the Critical GTP Sensors for GTP-Dependent Exocytosis

Gang Li,^1,2 Liping Han,^1,2 Ting-Chieh Chou,^1,2 Yoshihito Fujita,¹ Lakshmanan Arunachalam,^1,2 Ainan Xu,¹ Aaron Wong,¹ Soon-Kwang Chiew,¹ Qi Wan,^1,2 Li Wang,¹ and Shuzo Sugita^1,2

¹Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada M5T 2S8, and ²Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Correspondence should be addressed to Dr. Shuzo Sugita, Toronto Western Research Institute, MC11-432, University Health Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: ssugita{at}uhnres.utoronto.ca

Although it has been established that the activation of GTPases by non-hydrolyzable GTP stimulates neurotransmitter release from many different secretory cell types, the underlying mechanisms remain unclear. In the present study we aimed to elucidate the functional role(s) for endogenous Ras-like protein A (RalA) and RalB GTPases in GTP-dependent exocytosis. For this purpose stable neuroendocrine pheochromocytoma 12 (PC12) cell lines were generated in which the expressions of both RalA and RalB were strongly downregulated. In these double knock-down cells GTP-dependent exocytosis was reduced severely and was restored after the expression of RalA or RalB was reintroduced by transfection. In contrast, Ca²⁺-dependent exocytosis and the docking of dense core vesicles analyzed by electron microscopy remained unchanged in the double knock-down cells. Furthermore, the transfected RalA and RalB appeared to be localized primarily on the dense core vesicles in undifferentiated and nerve growth factor-differentiated PC12 cells. Our results indicate that endogenous RalA and RalB function specifically as GTP sensors for the GTP-dependent exocytosis of dense core vesicles, but they are not required for the general secretory pathways, including tethering of vesicles to the plasma membrane and Ca²⁺-dependent exocytosis.

Key words: exocytosis; Ral; exocyst; RNA interference; PC12 cells; dense core vesicles

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Received June 16, 2006; revised Nov. 6, 2006; accepted Nov. 27, 2006.

Correspondence should be addressed to Dr. Shuzo Sugita, Toronto Western Research Institute, MC11-432, University Health Network, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8. Email: ssugita{at}uhnres.utoronto.ca

This article has been cited by other articles:

				L. Arunachalam, L. Han, N. G. Tassew, Y. He, L. Wang, L. Xie, Y. Fujita, E. Kwan, B. Davletov, P. P. Monnier, et al. Munc18-1 Is Critical for Plasma Membrane Localization of Syntaxin1 but Not of SNAP-25 in PC12 Cells Mol. Biol. Cell, February 1, 2008; 19(2): 722 - 734. [Abstract] [Full Text] [PDF]

				Y. Fujita, A. Xu, L. Xie, L. Arunachalam, T.-C. Chou, T. Jiang, S.-K. Chiew, J. Kourtesis, L. Wang, H. Y. Gaisano, et al. Ca2+-dependent Activator Protein for Secretion 1 Is Critical for Constitutive and Regulated Exocytosis but Not for Loading of Transmitters into Dense Core Vesicles J. Biol. Chem., July 20, 2007; 282(29): 21392 - 21403. [Abstract] [Full Text] [PDF]

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