An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2+)-dependent regulation.

Worawan B Limpitikul,Ivy E Dick,Manu Ben-Johny,David T Yue

doi:10.1038/srep27235

Worawan B Limpitikul, Ivy E Dick + Show 2 more

Open Access

https://doi.org/10.1038/srep27235

Copy DOI

Abstract

CaV1.3 channels are a major class of L-type Ca2+ channels which contribute to the rhythmicity of the heart and brain. In the brain, these channels are vital for excitation-transcription coupling, synaptic plasticity, and neuronal firing. Moreover, disruption of CaV1.3 function has been associated with several neurological disorders. Here, we focus on the de novo missense mutation A760G which has been linked to autism spectrum disorder (ASD). To explore the role of this mutation in ASD pathogenesis, we examined the effects of A760G on CaV1.3 channel gating and regulation. Introduction of the mutation severely diminished the Ca2+-dependent inactivation (CDI) of CaV1.3 channels, an important feedback system required for Ca2+ homeostasis. This reduction in CDI was observed in two major channel splice variants, though to different extents. Using an allosteric model of channel gating, we found that the underlying mechanism of CDI reduction is likely due to enhanced channel opening within the Ca2+-inactivated mode. Remarkably, the A760G mutation also caused an opposite increase in voltage-dependent inactivation (VDI), resulting in a multifaceted mechanism underlying ASD. When combined, these regulatory deficits appear to increase the intracellular Ca2+ concentration, thus potentially disrupting neuronal development and synapse formation, ultimately leading to ASD.

Highlights

CaV1.3 channels are a major class of L-type Ca2+ channels which contribute to the rhythmicity of the heart and brain
The A760G mutation caused an opposite increase in voltagedependent inactivation (VDI), resulting in a multifaceted mechanism underlying autism spectrum disorders (ASD)
The S6 helices are known to contribute to VDI and Ca2+-dependent inactivation (CDI) in many CaV channels, including CaV1.314,40,42–50

Summary

Introduction

CaV1.3 channels are a major class of L-type Ca2+ channels which contribute to the rhythmicity of the heart and brain. CaV1.3 channels employ two major forms of feedback regulation, voltage-dependent inactivation (VDI) and Ca2+-dependent inactivation (CDI)[14] These two regulatory processes are controlled within each cell type, utilizing splice variation[3,15,16,17], RNA editing[18,19], and auxiliary subunit pairing[20,21] to tune the inactivation properties of the channel to specific cellular functions. Two gain-of-function mutations in CaV1.3 (G407R and A749G) have been linked to autism spectrum disorders (ASD)[30,31,37] Prior studies of these two mutations demonstrated alterations in channel gating including a hyperpolarizing shift in channel activation www.nature.com/scientificreports/

Methods

Results

Conclusion