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J. Biol. Chem., Vol. 282, Issue 45, 32877-32889, November 9, 2007

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Functional Interaction of Neuronal Ca_v1.3 L-type Calcium Channel with Ryanodine Receptor Type 2 in the Rat Hippocampus^*

Sunoh Kim, Hyung-Mun Yun, Ja-Hyun Baik, Kwang Chul Chung^¶, Seung-Yeol Nah^||, and Hyewhon Rhim¹

From the Life Sciences Division, Korea Institute of Science and Technology, Seoul 136-791, Graduate School of Biotechnology, Korea University, Seoul 136-701, the ^¶Department of Biology, College of Science, Yonsei University, Seoul 120-749, and the ^||Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Korea

Neuronal L-type Ca²⁺ channels do not support synaptic transmission, but they play an essential role in synaptic activity-dependent gene expression. Ca_v1.2 and Ca_v1.3 are the two most widely expressed L-type Ca²⁺ channels in neurons and have different biophysical and subcellular distributions. The function of the Ca_v 1.3 L-type Ca²⁺ channel and its cellular mechanisms in the central nervous system are poorly understood. In this study, using a yeast two-hybrid assay, we found that the N terminus of the rat Ca_v1.3 ₁ subunit interacts with a partial N-terminal amino acid sequence of ryanodine receptor type 2 (RyR2). Reverse transcription-PCR and Western blot assays revealed high expression of both Ca_v1.3 and RyR2 in the rat hippocampus. We also demonstrate a physical association of Ca_v1.3 with RyR2 using co-immunoprecipitation assays. Moreover, immunocytochemistry revealed prominent co-localization between Ca_v1.3 and RyR2 in hippocampal neurons. Depolarizing cells by an acute treatment of a high concentration of KCl (high-K, 60 mM) showed that the activation of L-type Ca²⁺ channels induced RyR opening and led to RyR-dependent Ca²⁺ release, even in the absence of extracellular Ca²⁺. Furthermore, we found that RyR2 mRNA itself is increased by long term treatment of high-K via activation of L-type Ca²⁺ channels. These acute and long term effects of high-K on RyRs were selectively blocked by small interfering RNA-mediated silencing of Ca_v1.3. These results suggest a physical and functional interaction between Ca_v1.3 and RyR2 and important implications of Ca_v1.3/RyR2 clusters in translating synaptic activity into alterations in gene expression.

Received for publication, February 16, 2007 , and in revised form, August 29, 2007.

^* This work was supported by KIST Core-Competence Program and Brain Research Center of the 21st Century Frontier Research Program Grant M103KV010007-07K2201-00710 (to H. R.), the Republic of Korea. 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: Life Sciences Division, Korea Institute of Science and Technology, 39-1 Hawholgok-dong, Sungbuk-gu, Seoul 136-791, Korea. Tel.: 82-2-958-5923; Fax: 82-2-958-5909; E-mail: hrhim{at}kist.re.kr.

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