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Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites

Abstract

In cells, molecular motors operate in polarized sorting of molecules, although the steering mechanisms of motors remain elusive1. In neurons, the kinesin motor2 conducts vesicular transport such as the transport of synaptic vesicle components to axons3 and of neurotransmitter receptors to dendrites4, indicating that vesicles may have to drive the motor for the direction to be correct. Here we show that an AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionate) receptor subunit—GluR2-interacting protein (GRIP1)—can directly interact and steer kinesin heavy chains to dendrites as a motor for AMPA receptors. As would be expected if this complex is functional, both gene targeting and dominant negative experiments of heavy chains of mouse kinesin showed abnormal localization of GRIP1. Moreover, expression of the kinesin-binding domain of GRIP1 resulted in accumulation of the endogenous kinesin predominantly in the somatodendritic area. This pattern was different from that generated by the overexpression of the kinesin-binding scaffold protein JSAP1 (JNK/SAPK-associated protein-1, also known as Mapk8ip3), which occurred predominantly in the somatoaxon area. These results indicate that directly binding proteins can determine the traffic direction of a motor protein.

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Figure 1: Kinesin binds to GRIP1, and is necessary for normal localization of GRIP1.
Figure 2: Kinesin–GRIP1–GluR2 complex in vivo.
Figure 3: KHCCBD relocates GRIP1 and GluR2.
Figure 4: The GRIP1 kinesin-binding site recruits kinesin to the soma and dendrites.

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Acknowledgements

We thank R. L. Huganir for the anti-GRIP1 and anti-GRIP2 antibodies, M. Mishina for anti-NR2B antibody, and M. Sheng for an anti-PanGRIP antibody. We thank Y. Hayashi for advice and for the Sindbis virus construction. We also thank Y. Hata, T. Nakagawa and M. Sheng for discussions; and H. Sato, H. Fukuda, T. Matsuki and M. Sugaya for technical assistance. Finally, we thank other members of the Hirokawa laboratory, especially T. Nakata, for technical assistance, discussions, and advice throughout the conducting of experiments. This work is supported by a Center of Excellence Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology of Japan to N. Hirokawa.

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Setou, M., Seog, DH., Tanaka, Y. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002). https://doi.org/10.1038/nature743

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