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LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary ?₂?-1 subunit.

ABSTRACT: Voltage-gated Ca²⁺ (Ca_V) channels consist of a pore-forming ?1 subunit, which determines the main functional and pharmacological attributes of the channel. The Ca_V1 and Ca_V2 channels are associated with auxiliary ?- and ?₂?-subunits. The molecular mechanisms involved in ?₂? subunit trafficking, and the effect of ?₂? subunits on trafficking calcium channel complexes remain poorly understood. Here we show that ?₂?-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes. This interaction with LRP1 is direct, and is modulated by the LRP chaperone, Receptor-Associated Protein (RAP). LRP1 regulates ?₂? binding to gabapentin, and influences calcium channel trafficking and function. Whereas LRP1 alone reduces ?₂?-1 trafficking to the cell-surface, the LRP1/RAP combination enhances mature glycosylation, proteolytic processing and cell-surface expression of ?₂?-1, and also increase plasma-membrane expression and function of Ca_V2.2 when co-expressed with ?₂?-1. Furthermore RAP alone produced a small increase in cell-surface expression of Ca_V2.2, ?₂?-1 and the associated calcium currents. It is likely to be interacting with an endogenous member of the LDL receptor family to have these effects. Our findings now provide a key insight and new tools to investigate the trafficking of calcium channel ?₂? subunits.

SUBMITTER: Kadurin I

PROVIDER: S-EPMC5335561 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α2δ-1 subunit.

Kadurin Ivan I Rothwell Simon W SW Lana Beatrice B Nieto-Rostro Manuela M Dolphin Annette C AC

Scientific reports 20170303

Voltage-gated Ca2+ (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2</su ...[more]

PMID: 28256585

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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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LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary ?₂?-1 subunit.

Publications

LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α<sub>2</sub>δ-1 subunit.

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Dataset Information

LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary ?2?-1 subunit.

Publications

LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α<sub>2</sub>δ-1 subunit.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary ?₂?-1 subunit.