ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Localized calcineurin confers Ca2+-dependent inactivation on neuronal L-type Ca2+ channels.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 61 citations in OpenAlex.
- Early life seizures chronically disrupt L-type voltage gated calcium channel regulation of mGluR mediated long term depression via interactions with protein phosphatase 2A.Neurobiology of disease · 2025Article
- Calcineurin inhibition may prevent Alzheimer disease in people with Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- Non-ionotropic voltage-gated calcium channel signaling.Channels (Austin, Tex.) · 2024Review
- Depolarization induces calcium-dependent BMP4 release from mouse embryonic palate mesenchymal cells.Nature communications · 2024Article
- Calcium-Associated Proteins in Neuroregeneration.Biomolecules · 2024Review
- Regulation of Cardiac Cav1.2 Channels by Calmodulin.International journal of molecular sciences · 2023Review
- A cellular atlas of calcineurin signaling.Biochimica et biophysica acta. Molecular cell research · 2023Review
- The CaNeuropharmacology · 2022Article
- Calcium and activity-dependent signaling in the developing cerebral cortex.Development (Cambridge, England) · 2022Review
- Mechanisms and physiological implications of cooperative gating of clustered ion channels.Physiological reviews · 2022Review
- Review
- Calcineurin in the heart: New horizons for an old friend.Cellular signalling · 2021Review
- Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation.The Journal of cell biology · 2021Article
- Protein Phosphatase 2B Dual Function Facilitates Synaptic Integrity and Motor Learning.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Review
- AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 CaFunction (Oxford, England) · 2021Article
- βAnnual review of pharmacology and toxicology · 2020Review
- Phosphorylation-Dependent Regulation of CaFrontiers in synaptic neuroscience · 2020Article
- A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type CaScientific reports · 2019Article
- Akt phosphorylation of neuronal nitric oxide synthase regulates gastrointestinal motility in mouse ileum.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
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Authors and funding
5 authors at 1 institution in 3 countries.
Funding
Abstract
Excitation-driven entry of Ca(2+) through L-type voltage-gated Ca(2+) channels controls gene expression in neurons and a variety of fundamental activities in other kinds of excitable cells. The probability of opening of Ca(V)1.2 L-type channels is subject to pronounced enhancement by cAMP-dependent protein kinase (PKA), which is scaffolded to Ca(V)1.2 channels by A-kinase anchoring proteins (AKAPs). Ca(V)1.2 channels also undergo negative autoregulation via Ca(2+)-dependent inactivation (CDI), which strongly limits Ca(2+) entry. An abundance of evidence indicates that CDI relies upon binding of Ca(2+)/calmodulin (CaM) to an isoleucine-glutamine motif in the carboxy tail of Ca(V)1.2 L-type channels, a molecular mechanism seemingly unrelated to phosphorylation-mediated channel enhancement. But our work reveals, in cultured hippocampal neurons and a heterologous expression system, that the Ca(2+)/CaM-activated phosphatase calcineurin (CaN) is scaffolded to Ca(V)1.2 channels by the neuronal anchoring protein AKAP79/150, and that overexpression of an AKAP79/150 mutant incapable of binding CaN (ΔPIX; CaN-binding PXIXIT motif deleted) impedes CDI. Interventions that suppress CaN activity-mutation in its catalytic site, antagonism with cyclosporine A or FK506, or intracellular perfusion with a peptide mimicking the sequence of the phosphatase's autoinhibitory domain-interfere with normal CDI. In cultured hippocampal neurons from a ΔPIX knock-in mouse, CDI is absent. Results of experiments with the adenylyl cyclase stimulator forskolin and with the PKA inhibitor PKI suggest that Ca(2+)/CaM-activated CaN promotes CDI by reversing channel enhancement effectuated by kinases such as PKA. Hence, our investigation of AKAP79/150-anchored CaN reconciles the CaM-based model of CDI with an earlier, seemingly contradictory model based on dephosphorylation signaling.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.