Dataset Information

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

ACCESS DATA

Publications

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

Similar Datasets

Project description:Calcium ion channels coordinate an astounding number of cellular functions. Surprisingly, only 10 Ca(V)alpha(1) subunit genes encode the structural cores of all voltage-gated calcium channels. What mechanisms exist to modify the structure of calcium channels and optimize their coupling to the rich spectrum of cellular functions? Growing evidence points to the contribution of post-translational alternative processing of calcium channel RNA as the main mechanism for expanding the functional potential of this important gene family. Alternative splicing of RNA is essential during neuronal development where fine adjustments in protein signaling promote and inhibit cell-cell interactions and underlie axonal guidance. However, attributing a specific functional role to an individual splice isoform or splice site has been difficult. In this regard, studies of ion channels are advantageous because their function can be monitored with precision, allowing even subtle changes in channel activity to be detected. Such studies are especially insightful when coupled with information about isoform expression patterns and cellular localization. In this paper, we focus on two sites of alternative splicing in the N-type calcium channel Ca(V)2.2 gene. We first describe cassette exon 18a that encodes a 21 amino acid segment in the II-III intracellular loop region of Ca(V)2.2. Here, we show that e18a is upregulated in the nervous system during development. We discuss these new data in light of our previous reports showing that e18a protects the N-type channel from cumulative inactivation. Second, we discuss our published data on exons e37a and e37b, which encode 32 amino acids in the intracellular C-terminus of Ca(V)2.2. These exons are expressed in a mutually exclusive manner. Exon e37a-containing Ca(V)2.2 mRNAs and their resultant channels express at higher density in dorsal root ganglia and, as we showed recently, e37a increases N-type channel sensitivity to G-protein-mediated inhibition, as compared to generic e37b-containing N-type channels.

Dataset Information

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

Dataset Information

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

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