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The Journal of Neuroscience, October 29, 2008, 28(44):11333-11346; doi:10.1523/JNEUROSCI.3078-08.2008

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Cellular/Molecular
The Role of MAP1A Light Chain 2 in Synaptic Surface Retention of Ca_V2.2 Channels in Hippocampal Neurons

A. G. Miriam Leenders,¹ Lin Lin,² Li-Dong Huang,² Claudia Gerwin,¹ Pei-Hua Lu,² and Zu-Hang Sheng¹

¹Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Bethesda, Maryland 20892-3701, and ²Department of Neurobiology, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China

Correspondence should be addressed to Zu-Hang Sheng, Synaptic Function Section, the Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Building 35, Room 3B203, 35 Convent Drive, Bethesda, MD 20892-3701. Email: shengz{at}ninds.nih.gov

Ca_v2.2 channels are localized at nerve terminals where they play a critical role in neurotransmission. However, the determinant that controls surface retention of these channels has not been identified. Here, we report that presynaptic surface localization of Ca_v2.2 is mediated through its interaction with light chain 2 (LC2) of microtubule-associated protein MAP1A. Deletion of a 23-residue binding domain within the Ca_v2.2 C terminus resulted in reduced synaptic distribution of the mutant channels. Using an antibody generated against an extracellular epitope of Ca_v2.2, we demonstrate that interfering the interaction with LC2 reduced surface expression of endogenous Ca_v2.2 at presynaptic boutons. In addition, the disruption of LC2–Ca_v2.2 coupling reduced Ca²⁺-influx into nerve terminals through Ca_v2.2 and impaired activity-dependent FM4-64 uptake. The treatments of neurons with Latrunculin A to disrupt actin filaments resulted in reduced density of surface Ca_v2.2-positive boutons. Furthermore, LC2NT, a LC2 truncated mutant lacking the actin-binding domain, could not rescue Ca_v2.2 surface expression after suppressing LC2 expression with RNAi. Because actin filaments are major cytomatric components at the presynaptic boutons, these observations suggest a mechanism by which LC2 provides anchoring of surface Ca_v2.2 to the actin cytoskeleton, thus contributing to presynaptic function.

Key words: calcium channels; presynaptic; surface expression; synaptic; axonal transport; microtubule; presynaptic regulation; actin

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Received July 2, 2008; revised Sept. 8, 2008; accepted Sept. 22, 2008.

Correspondence should be addressed to Zu-Hang Sheng, Synaptic Function Section, the Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke–National Institutes of Health, Building 35, Room 3B203, 35 Convent Drive, Bethesda, MD 20892-3701. Email: shengz{at}ninds.nih.gov

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