The DOI matches its Crossref record; 74 of the 75 references it cites were found in a registry or an index, and 1 are not checked yet.
Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics
Open accessAbstract
Increased cardiac contractility during the fight-or-flight response is caused by β-adrenergic augmentation of Ca V 1.2 voltage-gated calcium channels 1-4. However, this augmentation persists in transgenic murine hearts expressing mutant Ca V 1.2 α 1C and β subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of β-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which β-adrenergic agonists stimulate voltage-gated calcium channels. We express α 1C or β 2B subunits conjugated to ascorbate peroxidase 5 in mouse hearts, and use multiplexed quantitative proteomics 6,7 to track hundreds of proteins in the proximity of Ca V 1.2. We observe that the calcium-channel inhibitor Rad 8,9, a monomeric G protein, is enriched in the Ca V 1.2 microenvironment but is depleted during β-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for β subunits and relieves constitutive inhibition of Ca V 1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of Ca V 1.3 and Ca V 2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“proximity labelling to assess protein–protein interactions involved in β-adrenergic signalling of contractility in cardiac fight-or-flight responses124 and evaluation of regenerative stem cell therapy efficacy in post-infarct hearts125.”
From A high-stringency blueprint of the human proteome (2020) · cites this paper as [124]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Pérez-Riverol, Y., Csordas, A., Bai, J.-W., Bernal-Llinares, M., Hewapathirana, S., Kundu, D. J., Inuganti, A., Griss, J., Mayer, G., Eisenacher, M., et al. (2018) · Nucleic Acids Res. · doi:10.1093/nar/gky1106 · Cited by 6,216
Maere, S., Heymans, K., & Kuiper, M. T. R. (2005) · Computer applications in the biosciences · doi:10.1093/bioinformatics/bti551 · Cited by 4,163
Sequence and structure-based prediction of eukaryotic protein phosphorylation sites
Blom, N., Gammeltoft, S., & Brunak, S. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3310 · Cited by 3,212
PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)
Marx, S. O., Reiken, S. R., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., & Marks, A. R. (2000) · Cell · doi:10.1016/s0092-8674(00)80847-8 · Cited by 1,981
Self-citationA tissue-specific atlas of mouse protein phosphorylation and expression
Huttlin, E. L., Jedrychowski, M. P., Elias, J. E., Goswami, T., Rad, R., Beausoleil, S. A., Villén, J., Haas, W., Sowa, M. E., & Gygi, S. P. (2010) · Cell · doi:10.1016/j.cell.2010.12.001 · Cited by 1,778
Self-citationScansite 2.0: proteome-wide prediction of cell signaling interactions using short sequence motifs
Obenauer, J. C. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg584 · Cited by 1,609
Beausoleil, S. A., Villén, J., Gerber, S. A., Rush, J., & Gygi, S. P. (2006) · Nature Biotechnology · doi:10.1038/nbt1240 · Cited by 1,577
Self-citationThe importance of intrinsic disorder for protein phosphorylation
Iakoucheva, L. M. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh253 · Cited by 1,429
Directed evolution of APEX2 for electron microscopy and proximity labeling
Lam, S. S., Martell, J. D., Kamer, K. J., Deerinck, T. J., Ellisman, M. H., Mootha, V. K., & Ting, A. Y. (2014) · Nature Methods · doi:10.1038/nmeth.3179 · Cited by 1,395
Proteomic Mapping of Mitochondria in Living Cells via Spatially Restricted Enzymatic Tagging
Martell, J. D., Ting, A. Y., Rhee, H., Zou, P., Udeshi, N. D., Mootha, V. K., & Carr, S. A. (2012) · DSpace@MIT (Massachusetts Institute of Technology) · Cited by 1,330
Cited by
Sorted by citations
Deciphering molecular interactions by proximity labeling
Qin, W., Cho, K. F., Cavanagh, P. E., & Ting, A. Y. (2021) · Nature Methods · doi:10.1038/s41592-020-01010-5 · Cited by 671
Proximity labeling in mammalian cells with TurboID and split-TurboID
Cho, K. F., Branon, T. C., Udeshi, N. D., Myers, S. A., Carr, S. A., & Ting, A. Y. (2020) · Nature Protocols · doi:10.1038/s41596-020-0399-0 · Cited by 534
Presynaptic calcium channels: specialized control of synaptic neurotransmitter release
DOLPHIN, A. C., & Lee, A. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-0278-2 · Cited by 291
Varró, A., Tomek, J., Nagy, N., Virág, L., Passini, E., Rodríguez, B., & Baczkó, I. (2020) · Physiological Reviews · doi:10.1152/physrev.00024.2019 · Cited by 272
A high-stringency blueprint of the human proteome
Adhikari, S., Nice, E. C., Deutsch, E. W., Lane, L., Omenn, G. S., Pennington, S. R., Paik, Y.-K., Overall, C. M., Corrales, F. J., Cristea, I. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19045-9 · Cited by 210
Metadata
- Authors
- Liu, G., Papa, A., Katchman, A. N., Zakharov, S. I., Roybal, D., Hennessey, J. A., Kushner, J., Yang, L., Chen, B.-X., Kushnir, A., Dangas, K., Gygi, S. P., Pitt, G. S., Colecraft, H. M., Ben-Johny, M., Kalocsay, M., & Marx, S. O.
- Affiliations
- Columbia University (US)
- Harvard University (US)
- Weill Cornell Medicine (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Kalocsay, Marian
- Marx, Steven O.
- ORCID
- Venue
- Nature
- Published
- 2020-01-22
- Volume
- 577
- Issue
- 7792
- Pages
- 695-700
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7018383
- OpenAlex
- W3003002159
- Cited by
- 243
- References
- 74
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 36 · 2023: 36 · 2022: 39 · 2021: 50 · 2020: 28
- FWCI
- 12.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001873)
- National Heart, Lung, and Blood Institute (R01HL113136, F31HL142178, T32HL120826, R01HL126735, R01HL121253, R01HL140934, R01HL146149, T32HL160520, T32HL007343, T32HL007854)
- National Cancer Institute (P30CA013696)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- Cav1.2, voltage-gated calcium channels, beta-adrenergic signaling, protein kinase A, REM, G proteins, channel phosphorylation, channel inhibition, cardiac contractility, proximity proteomics, ascorbate peroxidase, Cav1.3, CaV2.2, calcium current
- MeSH terms
- Protein Domains, Cyclic AMP, Animals, Female, Humans, Male, Myocardium, Phosphorylation, Receptors, Adrenergic, beta, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, ras Proteins, Monomeric GTP-Binding Proteins, Calcium Channels, L-Type, Calcium Channels, N-Type, Heterotrimeric GTP-Binding Proteins, Protein Subunits, Proteomics, Mice, HEK293 Cells, Cellular Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
