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

Luna Gao,Qi Hall,Evan Ardiel,Joshua M Kaplan,Stephen Nurrish,Jian Zhao

doi:10.7554/elife.75140

Abstract

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 Caenorhabditis elegans 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 shn-1 mutants, SLO-2 currents and channel clustering are significantly decreased in both body muscles and neurons. Finally, increased and decreased shn-1 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.

Highlights

Shank is a synaptic scaffolding protein (Grabrucker et al, 2011)
SHN-1 acts in muscles to regulate action potential duration
Because SHN-1 directly binds EGL-19 (Pym et al, 2017), we asked if SHN-1 regulates muscle action potential (AP) firing patterns

Summary

Introduction

Shank is a synaptic scaffolding protein (containing SH3, PDZ, proline-rich and SAM domains) (Grabrucker et al, 2011). Mammals have three Shank genes, each encoding multiple isoforms (Jiang and Ehlers, 2013). Several mouse Shank knockouts have been described but these mutants exhibit inconsistent (often contradictory) synaptic and behavioral defects (Jiang and Ehlers, 2013), most likely resulting from differences in the Shank isoforms impacted by each mutation. Shank mutations alter synaptic function and behavior has not been determined. Shank mutations and CNVs are linked to Autism Spectrum Disorders (ASD), schizophrenia, and mania (Durand et al, 2007; Peca et al, 2011). Haploinsufficiency for 22q13 (which spans the Shank locus) occurs in Phelan-

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Discussion

Conclusion