An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca2+-dependent regulation

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.

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

“…Although we made no attempts to separate the contribution of CDI and VDI for inactivation, the decrease of τ slow must reflect a slowing of VDI by the mutation, whereas the increase in τ fast suggests a slowing of CDI. This agrees with the observation of reduced CDI and enhanced VDI of this mutation in a rat Cav1.3 splice variant [16]. The authors predicted that the increase in VDI by the mutation may act in opposition to the reduced of CDI.…”

“…We [9–12] and others [13–16] have recently described de novo missense mutations in CACNA1D encoding the pore-forming α1-subunit of Ca v 1.3 L-type channels. These included somatic mutations identified in aldosterone-producing adenomas [APAs, 11,12,15], as well as germline mutations from patients with neurodevelopmental disorders characterized by autism spectrum disorder (ASD) and/or intellectual disability with or without seizures [9,10,13–15].…”

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

“…Shank3 is the one of the most commonly mutated genes in individuals diagnosed with autism spectrum disorders (ASD) and is also linked to other neuropsychiatric disorders (Gauthier et al, 2010, Herbert, 2011. Functionally disruptive missense mutations in CaMKIIa and LTCCs have also been identified in patients with ASD and other neurodevelopmental disorders (Akita et al, 2018, Chia et al, 2018, Kury et al, 2017, Limpitikul et al, 2016, Moon et al, 2018, Nyegaard et al, 2010, Pinggera et al, 2015, Pinggera et al, 2017, Pinggera & Striessnig, 2016, Proietti Onori et al, 2018, Stephenson et al, 2017. In addition, the expression of c-fos, a well-studied target of CREB-mediated gene expression, is dysregulated in rodent models of autism (Dubiel & Kulesza, 2015, Orlandini et al, 1996, Williams & Umemori, 2014.…”

“…For example, Ca 2+ -dependent phosphorylation of the nuclear transcription factor CREB at Ser 133 leads to the transcription of immediate-early genes encoding multiple proteins (e.g., c-fos, BDNF, homer1a) that play key roles in learning and memory (Bading, 2013, Benito et al, 2011, Dolmetsch, 2003, Flavell & Greenberg, 2008. Multiple neuropsychiatric disorders are associated with disruptions in activity-dependent gene expression (Ebert & Greenberg, 2013, Gallo et al, 2018, and these disorders have been linked to mutations in Ca 2+ signaling proteins, such as L-type calcium channels (LTCCs) and calcium/calmodulin-dependent protein kinase II (CaMKII) (Akita et al, 2018, Chia et al, 2018, Kury et al, 2017, Limpitikul et al, 2016, Moon et al, 2018, Nyegaard et al, 2010, Pinggera et al, 2015, Pinggera et al, 2017, Pinggera & Striessnig, 2016, Proietti Onori et al, 2018, Stephenson et al, 2017. For example, Timothy Syndrome is caused by mutations in the CaV1.2 LTCC a1 subunit that disrupt neuronal excitation-transcription (E-T) coupling (Li et al, 2016), contributing to the neurobehavioral symptoms of this complex multi-system disorder, including autism spectrum disorder (ASD).…”

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

“…Multiple genes from this list are linked to neurological conditions. Calcium channel subunits Cacna1d and Cacna1a are associated with autism spectrum disorders (Limpitikul et al, 2016) and with familial hemiplegic migraine and episodic ataxia (Grieco et al, 2018;Jen and Wan, 2018), respectively. Variants in the Gria4 gene are linked to schizophrenia and intellectual disability (Makino et al, 2003;MacDonald et al, 2015;Martin et al, 2017).…”