Dataset Information

The ?2?-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with ?2?-1.

ABSTRACT: Voltage-gated calcium channel auxiliary ?2? subunits are important for channel trafficking and function. Here, we compare the effects of ?2?-1 and an ?2?-like protein called Cachd1 on neuronal N-type (CaV2.2) channels, which are important in neurotransmission. Previous structural studies show the ?2?-1 VWA domain interacting with the first loop in CaV1.1 domain-I via its metal ion-dependent adhesion site (MIDAS) motif and additional Cache domain interactions. Cachd1 has a disrupted MIDAS motif. However, Cachd1 increases CaV2.2 currents substantially (although less than ?2?-1) and increases CaV2.2 cell surface expression by reducing endocytosis. Although the effects of ?2?-1 are abolished by mutation of Asp122 in CaV2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with CaV2.2 and inhibits co-immunoprecipitation of ?2?-1 by CaV2.2. Cachd1 also competes with ?2?-1 for effects on trafficking. Thus, Cachd1 influences both CaV2.2 trafficking and function and can inhibit responses to ?2?-1.

SUBMITTER: Dahimene S

PROVIDER: S-EPMC6231325 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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The α2δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α2δ-1.

Dahimene Shehrazade S Page Karen M KM Kadurin Ivan I Ferron Laurent L Ho Dominique Y DY Powell Gareth T GT Pratt Wendy S WS Wilson Stephen W SW Dolphin Annette C AC

Cell reports 20181101 6

Voltage-gated calcium channel auxiliary α2δ subunits are important for channel trafficking and function. Here, we compare the effects of α2δ-1 and an α2δ-like protein called Cachd1 on neuronal N-type (CaV2.2) channels, which are important in neurotransmission. Previous structural studies show the α2δ-1 VWA domain interacting with the first loop in CaV1.1 domain-I via its metal ion-dependent adhesion site (MIDAS) motif and additional Cache domain interactions. Cachd1 has a d ...[more]

PMID: 30404013

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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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Dataset Information

The ?2?-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with ?2?-1.

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The α<sub>2</sub>δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α<sub>2</sub>δ-1.

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Dataset Information

The ?2?-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with ?2?-1.

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The α&lt;sub&gt;2&lt;/sub&gt;δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α&lt;sub&gt;2&lt;/sub&gt;δ-1.

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OmicsDI is part of the ELIXIR infrastructure

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The α<sub>2</sub>δ-like Protein Cachd1 Increases N-type Calcium Currents and Cell Surface Expression and Competes with α<sub>2</sub>δ-1.