Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity.
Functional crosstalk between cell-surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)-mediated Ca(2+)-induced Ca(2+) release and the subsequent opening of small-conductance Ca(2+)-activated K(+) (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP-DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long-term depression (LTD) at parallel fiber-PC synapses adversely established long-term potentiation in the JP-DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP-DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca(2+)-mediated communication between voltage-gated Ca(2+) channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.
Kakizawa
Sho
S
Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Kishimoto
Yasushi
Y
Hashimoto
Kouichi
K
Miyazaki
Taisuke
T
Furutani
Kazuharu
K
Shimizu
Hidemi
H
Fukaya
Masahiro
M
Nishi
Miyuki
M
Sakagami
Hiroyuki
H
Ikeda
Atsushi
A
Kondo
Hisatake
H
Kano
Masanobu
M
Watanabe
Masahiko
M
Iino
Masamitsu
M
Takeshima
Hiroshi
H
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015640:Ion Channel Gating; D007858:Learning; D036881:Long-Term Synaptic Depression; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009048:Motor Skills / Q000502:physiology; D009473:Neuronal Plasticity; D011689:Purkinje Cells / Q000166:cytology* / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D008565:Membrane Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D051640:Small-Conductance Calcium-Activated Potassium Channels; C412507:junctophilin; D002118:Calcium