Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway
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Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway. / Jensen, Camilla Stampe; Watanabe, Shoji; Stas, Jeroen Ingrid; Klaphaak, Jessica; Yamane, Ayaka; Schmitt, Nicole; Olesen, Søren-Peter; Trimmer, James S; Rasmussen, Hanne Borger; Misonou, Hiroaki.
In: The Journal of neuroscience : the official journal of the Society for Neuroscience, Vol. 37, No. 48, 29.11.2017, p. 11523-11536.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - Trafficking of Kv2.1 Channels to the Axon Initial Segment by a Novel Nonconventional Secretory Pathway
AU - Jensen, Camilla Stampe
AU - Watanabe, Shoji
AU - Stas, Jeroen Ingrid
AU - Klaphaak, Jessica
AU - Yamane, Ayaka
AU - Schmitt, Nicole
AU - Olesen, Søren-Peter
AU - Trimmer, James S
AU - Rasmussen, Hanne Borger
AU - Misonou, Hiroaki
N1 - Copyright © 2017 the authors 0270-6474/17/3711523-14$15.00/0.
PY - 2017/11/29
Y1 - 2017/11/29
N2 - Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.SIGNIFICANCE STATEMENT Our study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.
AB - Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in high-density cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability.SIGNIFICANCE STATEMENT Our study uncovered a novel mechanism that targets the Kv2.1 voltage-gated potassium channel to two distinct trafficking pathways and two distinct subcellular destinations: the somatodendritic plasma membrane and that of the axon initial segment. We also identified a distinct motif, including putative phosphorylation sites, that is important for the AIS localization. This raises the possibility that the destination of a channel protein can be dynamically regulated via changes in post-translational modification, which would impact the excitability of specific membrane compartments.
KW - Animals
KW - Axon Initial Segment
KW - Cell Membrane
KW - Cells, Cultured
KW - Female
KW - HEK293 Cells
KW - Hippocampus
KW - Humans
KW - Male
KW - Neurons
KW - Protein Transport
KW - Rats
KW - Secretory Pathway
KW - Shab Potassium Channels
KW - Journal Article
U2 - 10.1523/JNEUROSCI.3510-16.2017
DO - 10.1523/JNEUROSCI.3510-16.2017
M3 - Journal article
C2 - 29042434
VL - 37
SP - 11523
EP - 11536
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
SN - 0270-6474
IS - 48
ER -
ID: 189625068