Shank promotes action potential repolarization by recruiting BK channels to calcium microdomains

Mutations altering the scaffolding protein Shank are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. Among its many binding partners, Shank directly binds CaV1 voltage activated calcium channels. Here, we show that the SHN-1/Shank promotes CaV1 coupling to ca...

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Bibliographic Details
Published in:eLife 2022-03, Vol.11
Main Authors: Gao, Luna, Zhao, Jian, Ardiel, Evan, Hall, Qi, Nurrish, Stephen, Kaplan, Joshua M
Format: Article
Language:English
Subjects:
Action potential
Action Potentials
Animals
BK channel
Caenorhabditis elegans - genetics
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
Calcium - metabolism
Calcium channels
Calcium channels (voltage-gated)
Calcium, Dietary
Carrier Proteins - metabolism
Copy number
Humans
Large-Conductance Calcium-Activated Potassium Channels - genetics
Large-Conductance Calcium-Activated Potassium Channels - metabolism
Localization
Mammals
Membrane Transport Proteins - metabolism
Mental disorders
Mental illness
Mice
Muscles
Mutation
Neuroscience
Potassium
Potassium channels
Potassium channels (calcium-gated)
Proteins
Schizophrenia
shank
SHN-1
SLO-1
SLO-2
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Summary:Mutations altering the scaffolding protein Shank are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. Among its many binding partners, Shank directly binds CaV1 voltage activated calcium channels. Here, we show that the SHN-1/Shank promotes CaV1 coupling to calcium activated potassium channels. Mutations inactivating SHN-1, and those preventing SHN-1 binding to EGL-19/CaV1 all increase action potential durations in body muscles. Action potential repolarization is mediated by two classes of potassium channels: SHK-1/KCNA and SLO-1 and SLO-2 BK channels. BK channels are calcium-dependent, and their activation requires tight coupling to EGL-19/CaV1 channels. SHN-1's effects on AP duration are mediated by changes in BK channels. In mutants, SLO-2 currents and channel clustering are significantly decreased in both body muscles and neurons. Finally, increased and decreased gene copy number produce similar changes in AP width and SLO-2 current. Collectively, these results suggest that an important function of Shank is to promote microdomain coupling of BK with CaV1.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.75140