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 (Ca2.2) channels, which are important in neurotransmission. Previous structural studies show the α2δ-1 VWA domain interacting with the first loop in Ca1.1 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 Ca2.2 currents substantially (although less than α2δ-1) and increases Ca2.2 cell surface expression by reducing endocytosis. Although the effects of α2δ-1 are abolished by mutation of Asp122 in Ca2.2 domain-I, which mediates interaction with its VWA domain, the Cachd1 responses are unaffected. Furthermore, Cachd1 co-immunoprecipitates with Ca2.2 and inhibits co-immunoprecipitation of α2δ-1 by Ca2.2. Cachd1 also competes with α2δ-1 for effects on trafficking. Thus, Cachd1 influences both Ca2.2 trafficking and function and can inhibit responses to α2δ-1.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231325 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2018.10.033 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Clues into Wnt cell surface signalosomes and its biogenesis.
Trends Biochem Sci
December 2024
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:
Wnt morphogens induce signaling via binding their extracellular receptors. Here, we discuss several recent structural studies showing how Wnts engage their receptors frizzled (FZD) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6), how Cachd1 has been shown as an alternative initiator of Wnt signaling, and how lipidated Wnt may be produced and secreted from the cell.
View Article and Find Full Text PDFCachd1 interacts with Wnt receptors and regulates neuronal asymmetry in the zebrafish brain.
Science
May 2024
Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
Neurons on the left and right sides of the nervous system often show asymmetric properties, but how such differences arise is poorly understood. Genetic screening in zebrafish revealed that loss of function of the transmembrane protein Cachd1 resulted in right-sided habenula neurons adopting left-sided identity. Cachd1 is expressed in neuronal progenitors, functions downstream of asymmetric environmental signals, and influences timing of the normally asymmetric patterns of neurogenesis.
View Article and Find Full Text PDFBiallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities.
Genet Med
April 2024
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA. Electronic address:
Article Synopsis
- Researchers identified a genetic cause for a rare neurodevelopmental syndrome characterized by cognitive impairment, distinctive facial features, and various additional health issues.
- They studied six individuals from unrelated families using exome sequencing and created models with human stem cells and zebrafish to examine the effects of the identified gene, CACHD1.
- Results showed that mutations in CACHD1 lead to significant neural development problems and physical defects, linking it directly to the syndrome’s symptoms.
Natural variation in gene expression and viral susceptibility revealed by neural progenitor cell villages.
Cell Stem Cell
March 2023
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
Human genome variation contributes to diversity in neurodevelopmental outcomes and vulnerabilities; recognizing the underlying molecular and cellular mechanisms will require scalable approaches. Here, we describe a "cell village" experimental platform we used to analyze genetic, molecular, and phenotypic heterogeneity across neural progenitor cells from 44 human donors cultured in a shared in vitro environment using algorithms (Dropulation and Census-seq) to assign cells and phenotypes to individual donors. Through rapid induction of human stem cell-derived neural progenitor cells, measurements of natural genetic variation, and CRISPR-Cas9 genetic perturbations, we identified a common variant that regulates antiviral IFITM3 expression and explains most inter-individual variation in susceptibility to the Zika virus.
View Article and Find Full Text PDFαδ-4 and Cachd1 Proteins Are Regulators of Presynaptic Functions.
Int J Mol Sci
August 2022
Institute of Physiology, Medical University Innsbruck, 6020 Innsbruck, Austria.
The αδ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, αδ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!