Dataset Information

Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment.

ABSTRACT: The voltage-gated Kv7.2/Kv7.3 potassium channel is a critical regulator of neuronal excitability. It is strategically positioned at the axon initial segment (AIS) of neurons, where it effectively inhibits repetitive action potential firing. While the selective accumulation of Kv7.2/Kv7.3 channels at the AIS requires binding to the adaptor protein ankyrin G, it is currently unknown if additional molecular mechanisms contribute to the localization and fine-tuning of channel numbers at the AIS. Here, we utilized a chimeric approach to pinpoint regions within the Kv7.3 C-terminal tail with an impact upon AIS localization. This strategy identified two domains with opposing effects upon the AIS localization of Kv7.3 chimeras expressed in cultured hippocampal neurons. While a membrane proximal domain reduced AIS localization of Kv7.3 chimeras, helix D increased and stabilized chimera AIS localization. None of the identified domains were required for AIS localization. However, the domains modulated the relative efficiency of the localization raising the possibility that the two domains contribute to the regulation of Kv7 channel numbers and nanoscale organization at the AIS.

SUBMITTER: Hefting LL

PROVIDER: S-EPMC7010958 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment.

Hefting Louise Leth LL D'Este Elisa E Arvedsen Emil E Benned-Jensen Tau T Rasmussen Hanne Borger HB

Frontiers in cellular neuroscience 20200204

The voltage-gated Kv7.2/Kv7.3 potassium channel is a critical regulator of neuronal excitability. It is strategically positioned at the axon initial segment (AIS) of neurons, where it effectively inhibits repetitive action potential firing. While the selective accumulation of Kv7.2/Kv7.3 channels at the AIS requires binding to the adaptor protein ankyrin G, it is currently unknown if additional molecular mechanisms contribute to the localization and fine-tuning of channel numbers at the AIS. Her ...[more]

PMID: 32116557

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Project description:Abstract Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analysed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e. axon initial segment length and position. We found that the axon initial segment length was increased only in pyramidal neurons of inactive demyelinated lesions, compared with normal appearing grey matter tissue. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show, for the first time, changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function. Dilsizoglu Senol et al. highlight the importance of the axon initial segment in multiple sclerosis by demonstrating its shift away from the soma in both the neocortex and the cerebellum of multiple sclerosis active and inactive lesions and by showing evidence that this change could alter neuronal function. Graphical Abstract Graphical Abstract

Dataset Information

Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment.

Publications

Multiple Domains in the Kv7.3 C-Terminus Can Regulate Localization to the Axon Initial Segment.

Similar Datasets

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