T-type calcium channels functionally interact with spectrin (α/β) and ankyrin B

Garcı́a-Caballero, Agustı́n; Zhang, Fang-Xiong; Hodgkinson, Victoria; Huang, Junting; Chen, Lina; Souza, Ivana A.; Cain, Stuart M.; Kass, Jennifer; Alles, Sascha R.A.; Snutch, Terrance P.; Zamponi, Gerald W.

doi:10.1186/s13041-018-0368-5

Cited by 14 publications

(7 citation statements)

References 42 publications

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“…2). Regulation of Cav3 channels by such endogenous proteins would more likely reflect the numerous signalling pathways targeting Cav3 channels, as reported for the G protein βγ-dimer [50,162], calmodulin [33,86], syntaxin-1A [159], and spectrin α/β and ankyrin B [61] (Fig. 2).…”

Section: Cav3 Modulationmentioning

confidence: 77%

Neuronal Cav3 channelopathies: recent progress and perspectives

Lory

Nicole

Monteil

2020

Pflugers Arch - Eur J Physiol

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T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knockout mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.

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Section: Cav3 Modulationmentioning

confidence: 77%

Neuronal Cav3 channelopathies: recent progress and perspectives

Lory

Nicole

Monteil

2020

Pflugers Arch - Eur J Physiol

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“…Although β- and γ-ENaC subunits consistently co-immnoprecipitate with Cav3.2 calcium channels from different neuronal tissues, we do not exclude the possibility that other protein partners are directly involved in the formation of Cav3.2 / ENaC complexes. For example, we have recently shown that Cav3.2 calcium channels can be clustered at the plasma membrane via spectrin / ankyrin B binding [26]. Spectrin is a highly abundant cytoskeletal protein in the nervous system [27, 28] and ENaC can also bind to both ankyrin and spectrin [29, 30], suggesting these cytoskeletal elements as a possible link between these channels.…”

Section: Discussionmentioning

confidence: 99%

Cav3.2 calcium channel interactions with the epithelial sodium channel ENaC

et al. 2019

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This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β-ENaC subunits showed overlapping expression with endogenous Cav3.2 calcium channels in the thalamus and hypothalamus as detected by immunostaining. Moreover, β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Mutation of a cluster of lysines present in the intracellular N-terminus region of β-ENaC (K4R/ K5R/ K9R/ K16R/ K23R) reduced interactions with Cav3.2 calcium channels. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. T-type current density was increased when fully assembled αβγ-ENaC channels were transiently expressed in CAD cells, a neuronal derived cell line. Altogether, these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues.Electronic supplementary materialThe online version of this article (10.1186/s13041-019-0433-8) contains supplementary material, which is available to authorized users.

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“…It has been long established that spectrins and integrins play important roles in the synaptic transmission (Chavis and Westbrook, 2001;Goodman, 1999), including the gating of neurotransmitter release (Featherstone et al, 2001;Huang et al, 2006). Presynaptic integrin and spectrin subtypes have been directly implicated in interactions with voltage-gated Ca 2+ channels and AZ components (Carlson et al, 2010;Garcia-Caballero et al, 2018;Khanna et al, 2007a;Khanna et al, 2007b). Nonetheless, a role for ligand-activated integrin in the synaptic recruitment of spectrin has not been previously reported.…”

Section: Discussionmentioning

confidence: 99%

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

Wang

Friend

Vicidomini

et al. 2019

Preprint

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We have previously reported that Drosophila Tenectin (Tnc) recruits PS2/PS integrin to ensure structural and functional integrity at larval NMJs (Wang et al., 2018). In muscles, Tnc/integrin engages the spectrin network to regulate the size and architecture of synaptic boutons. In neurons, Tnc/integrin controls neurotransmitter release. Here we show that presynaptic Tnc/integrin modulates the synaptic accumulation of key active zone components, including the Ca 2+ channel Cac and the active zone scaffold Brp. Presynaptic α-Spectrin appears to be both required and sufficient for the recruitment of Cac and Brp. We visualized the endogenous α-Spectrin and found that Tnc controls spectrin recruitment at synaptic terminals. Thus, Tnc/integrin anchors the presynaptic spectrin network and ensures the proper assembly and function of the active zones. Since pre-and postsynaptic Tnc/integrin limit each other, we hypothesize that this pathway links dynamic changes within the synaptic cleft to changes in synaptic structure and function. The synaptic extracellular matrix (ECM) contains various synaptic organizers and diffusible molecules that establish and modify synaptic connections during development. ECM receptors, including integrins, transduce these signals by sensing the changes in the synaptic environment and orchestrating the appropriate changes in synapse structure and function (Chavis and Westbrook, 2001;Huang et al., 2006). Disruption of integrins impair synapse development and maturation, neurotransmission, and long-term synaptic plasticity (reviewed in (Park and Goda, 2016)). Integrins together with their ECM ligands form complexes with cytoskeletal proteins and active zone (AZ) components (Carlson et al., 2010;Nishimune et al., 2004;Sunderland et al., 2000). However, it remains unclear how these interactions could influence neurotransmitter release.Spectrin, a principal component of the membrane skeleton, is critical for synaptic transmission (Featherstone et al., 2001;Goodman, 1999). Spectrin subunits function as docking platforms for membrane channels, neurotransmitter receptors and adhesion molecules (reviewed in (Machnicka et al., 2014)). For example, spectrins associate with presynaptic Ca 2+ channels in synaptosome lysates (Carlson et al., 2010;Khanna et al., 2007a;Khanna et al., 2007b). Also, a spectrin-containing presynaptic web enables AZ function in the rodent CNS (Phillips et al., 2001). Recent super-resolution fluorescence microscopy uncovered periodic actin/spectrin lattices along axons, dendrites and spines in a broad range of neuronal cell types (He et al., 2016;Qu et al., 2017;Xu et al., 2013); however, at presynaptic and postsynaptic sites, these patterns were absent (Sidenstein et al., 2016).We have previously found that Drosophila Tenectin (Tnc), an integrin ligand that accumulates in the synaptic cleft at the larval NMJ, modulates synapse development and function (Wang et al., 2018). Tnc recruits αPS2/βPS integrin and forms cis active complexes with distinct pre-and post-synaptic functions....

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T-type calcium channels functionally interact with spectrin (α/β) and ankyrin B

Cited by 14 publications

References 42 publications

Neuronal Cav3 channelopathies: recent progress and perspectives

Neuronal Cav3 channelopathies: recent progress and perspectives

Cav3.2 calcium channel interactions with the epithelial sodium channel ENaC

A presynaptic spectrin network controls active zone assembly and neurotransmitter release

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