TY - JOUR
T1 - An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca2+ -dependent regulation
AU - Limpitikul, Worawan B.
AU - Dick, Ivy E.
AU - Ben-Johny, Manu
AU - Yue, David T.
N1 - Funding Information:
We are grateful to Dr. Evan E. Eichler for investigating the previously unreported clinical phenotype of the proband and generously sharing relevant results with us. We thank Wanjun Yang for dedicated technical support and Ingie Hong for providing us with neuronal stimulus waveforms and experimental input. We also thank Gordon Tomaselli for providing valuable advice and discussions, and members of the Calcium Signals Lab for ongoing feedback. This work was supported by grants NIMH R01MH065531 and NHLBI 5R37HL076795 (D.T.Y.).
PY - 2016/6/3
Y1 - 2016/6/3
N2 - 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.
AB - 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.
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U2 - 10.1038/srep27235
DO - 10.1038/srep27235
M3 - Article
AN - SCOPUS:84973395018
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 27235
ER -