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Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α₂δ-1 but not α₂δ-3.

ABSTRACT: N-type voltage-gated calcium channels (Ca_V2.2) are predominantly expressed at presynaptic terminals, and their function is regulated by auxiliary α₂δ and β subunits. All four mammalian α₂δ subunits enhance calcium currents through Ca_V1 and Ca_V2 channels, and this increase is attributed, in part, to increased Ca_V expression at the plasma membrane. In the present study we provide evidence that α₂δ-1, like α₂δ-2, is recycled to the plasma membrane through a Rab11a-dependent endosomal recycling pathway. Using a dominant-negative Rab11a mutant, Rab11a(S25N), we show that α₂δ-1 increases plasma membrane Ca_V2.2 expression by increasing the rate and extent of net forward Ca_V2.2 trafficking in a Rab11a-dependent manner. Dominant-negative Rab11a also reduces the ability of α₂δ-1 to increase Ca_V2.2 expression on the cell-surface of hippocampal neurites. In contrast, α₂δ-3 does not enhance rapid forward Ca_V2.2 trafficking, regardless of whether Rab11a(S25N) is present. In addition, whole-cell Ca_V2.2 currents are reduced by co-expression of Rab11a(S25N) in the presence of α₂δ-1, but not α₂δ-3. Taken together these data suggest that α₂δ subtypes participate in distinct trafficking pathways which in turn influence the localisation and function of Ca_V2.2.

SUBMITTER: Meyer JO

PROVIDER: S-EPMC8119971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α₂δ-1 but not α₂δ-3.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α2δ-1 but not α2δ-3.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Rab11-dependent recycling of calcium channels is mediated by auxiliary subunit α₂δ-1 but not α₂δ-3.