TY - JOUR
T1 - Molecular Motor KIF5A Is Essential for GABAA Receptor Transport, and KIF5A Deletion Causes Epilepsy
AU - Nakajima, Kazuo
AU - Yin, Xiling
AU - Takei, Yosuke
AU - Seog, Dae Hyun
AU - Homma, Noriko
AU - Hirokawa, Nobutaka
N1 - Funding Information:
We are grateful to Josef Kittler (University College London), Chitoshi Takayama (University of the Ryukyus), and Masato Hirata (Kyushu University) for kindly providing the GFP-tagged GABA A R constructs, antibodies against GABA A R subunits, and plasmids for GABARAP, respectively. We also thank Yosuke Tanaka, Ying Tong, and Yayoi Kikkawa for assistance in generating the knockout mouse; Yoshimitsu Kanai, Shinsuke Niwa, and Kazuhiko Mitsumori for technical assistance; and H. Sato, H. Fukuda, N. Onouchi, T. Akamatsu, T. Aizawa, and all other members of the Hirokawa laboratory for assistance. This work was supported by a Grant-in-Aid for specially promoted research to N.H. from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Korean Ministry of Education, Science and Technology (2012-007530, to D.-H.S.).
PY - 2012/12/6
Y1 - 2012/12/6
N2 - KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a-knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABAA receptor (GABAAR)-mediated synaptic transmission. We also identified reduced cell surface expression of GABAAR in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABAAR-associated protein (GABARAP) that is known to be involved in GABAAR trafficking. KIF5A regulated neuronal surface expression of GABAARs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission.
AB - KIF5 (also known as kinesin-1) family members, consisting of KIF5A, KIF5B, and KIF5C, are microtubule-dependent molecular motors that are important for neuronal function. Among the KIF5s, KIF5A is neuron specific and highly expressed in the central nervous system. However, the specific roles of KIF5A remain unknown. Here, we established conditional Kif5a-knockout mice in which KIF5A protein expression was postnatally suppressed in neurons. Epileptic phenotypes were observed by electroencephalogram abnormalities in knockout mice because of impaired GABAA receptor (GABAAR)-mediated synaptic transmission. We also identified reduced cell surface expression of GABAAR in knockout neurons. Importantly, we identified that KIF5A specifically interacted with GABAAR-associated protein (GABARAP) that is known to be involved in GABAAR trafficking. KIF5A regulated neuronal surface expression of GABAARs via an interaction with GABARAP. These results provide an insight into the molecular mechanisms of KIF5A, which regulate inhibitory neural transmission.
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U2 - 10.1016/j.neuron.2012.10.012
DO - 10.1016/j.neuron.2012.10.012
M3 - Article
C2 - 23217743
AN - SCOPUS:84872739997
SN - 0896-6273
VL - 76
SP - 945
EP - 961
JO - Neuron
JF - Neuron
IS - 5
ER -