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Proteolytic maturation of ?₂? represents a checkpoint for activation and neuronal trafficking of latent calcium channels.

ABSTRACT: The auxiliary ?₂? subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides ?₂ and ?. We now show, using ?₂? constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (Ca_V2.2) calcium channels. Indeed, uncleaved ?2? inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of ?₂?, voltage-dependent activation of channels is promoted, independent from the trafficking role of ?₂?. Uncleaved ?₂? does not support trafficking of Ca_V2.2 channel complexes into neuronal processes, and inhibits Ca²⁺ entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved ?₂? subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of ?₂? then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes.

SUBMITTER: Kadurin I

PROVIDER: S-EPMC5092059 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels.

Kadurin Ivan I Ferron Laurent L Rothwell Simon W SW Meyer James O JO Douglas Leon R LR Bauer Claudia S CS Lana Beatrice B Margas Wojciech W Alexopoulos Orpheas O Nieto-Rostro Manuela M Pratt Wendy S WS Dolphin Annette C AC

eLife 20161026

The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using α2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents i ...[more]

PMID: 27782881

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Project description:Auxiliary α2δ subunits of voltage-gated calcium channels modulate channel trafficking, current properties, and synapse formation. Three of the four isoforms (α2δ-1, α2δ-2, and α2δ-3) are abundantly expressed in the brain; however, of the available knockout models, only α2δ-2 knockout or mutant mice display an obvious abnormal neurological phenotype. Thus, we hypothesize that the neuronal α2δ isoforms may have partially specific as well as redundant functions. To address this, we generated three distinct α2δ double knockout mouse models by crossbreeding single knockout (α2δ-1 and -3) or mutant (α2δ-2/ducky) mice. Here, we provide a first phenotypic description and brain structure analysis. We found that genotypic distribution of neonatal litters in distinct α2δ-1/-2, α2δ-1/-3, and α2δ-2/-3 breeding combinations did not conform to Mendel's law, suggesting premature lethality of single and double knockout mice. Notably, high occurrences of infant mortality correlated with the absence of specific α2δ isoforms (α2Δ-2 > α2δ-1 > α2δ-3), and was particularly observed in cages with behaviorally abnormal parenting animals of α2δ-2/-3 cross-breedings. Juvenile α2δ-1/-2 and α2δ-2/-3 double knockout mice displayed a waddling gate similar to ducky mice. However, in contrast to ducky and α2δ-1/-3 double knockout animals, α2δ-1/-2 and α2δ-2/-3 double knockout mice showed a more severe disease progression and highly impaired development. The observed phenotypes within the individual mouse lines may be linked to differences in the volume of specific brain regions. Reduced cortical volume in ducky mice, for example, was associated with a progressively decreased space between neurons, suggesting a reduction of total synaptic connections. Taken together, our findings show that α2δ subunits differentially regulate premature survival, postnatal growth, brain development, and behavior, suggesting specific neuronal functions in health and disease.

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Proteolytic maturation of ?₂? represents a checkpoint for activation and neuronal trafficking of latent calcium channels.

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Proteolytic maturation of α<sub>2</sub>δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels.

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Proteolytic maturation of ?2? represents a checkpoint for activation and neuronal trafficking of latent calcium channels.

Publications

Proteolytic maturation of α<sub>2</sub>δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Proteolytic maturation of ?₂? represents a checkpoint for activation and neuronal trafficking of latent calcium channels.