The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944
Open accessPublished version of a preprint
Abstract
Among the three classes of voltage-gated Ca2+ channels (CaV1, CaV2, and CaV3), CaV3 T-type channels are drug targets for disorders, including epilepsy and pain. Antagonists such as Z944 and ML218 are highly selective for CaV3 compared with the CaV1.2 L-type channel, but whether they have additional activity on other CaV1 subtypes is unknown. Here, we investigated the effects of Z944 and ML218 on the CaV1.4 channel, which regulates neurotransmitter release from retinal photoreceptors. In HEK293T cells transfected with CaV1.4 and the auxiliary β2x13 and α2δ-4 subunits, Z944 and ML218 inhibited Ca2+ currents with IC50 values of ∼30 and 2 µM, respectively. Structure-based modeling combined with functional studies revealed the importance of a cluster of methionine residues, particularly M1004, within the DHP-binding site for the effects of ML218. Compared with mutation of a conserved threonine (T1007) that is required for DHP sensitivity of CaV1 channels, mutation of M1004 had a 10-fold greater impact in diminishing the potency of ML218. CaV1.2 was significantly less sensitive to ML218 inhibition (IC50 ∼37 µM) than CaV1.4, which could not be attributed to a valine in place of M1004 in CaV1.2. We conclude that ML218 and Z944 are dual CaV1/CaV3 modulators of CaV1.4 and should be used with caution when dissecting the contributions of CaV3 channels in tissues where CaV1.4 is expressed.
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.
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
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels
Perez‐Reyes, E. (2003) · Physiological Reviews · doi:10.1152/physrev.00018.2002 · Cited by 1,655
Zamponi, G. W., Striessnig, J., Koschak, A., & DOLPHIN, A. C. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.009654 · Cited by 1,157
Novel dihydropyridines with positive inotropic action through activation of Ca2+ channels
Schramm, M., Thomas, G., Towart, R., & Franckowiak, G. (1983) · Nature · doi:10.1038/303535a0 · Cited by 1,003
Llinas, R. H., & Yarom, Y. (1981) · The Journal of Physiology · doi:10.1113/jphysiol.1981.sp013763 · Cited by 972
Huguenard, J., & Prince, D. A. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-10-03804.1992 · Cited by 563
ROSETTALIGAND: Protein–small molecule docking with full side‐chain flexibility
Meiler, J., & Baker, D. A. (2006) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21086 · Cited by 508
Xu, W., & Lipscombe, D. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-16-05944.2001 · Cited by 485
α1D (Cav1.3) Subunits Can Form L-type Ca2+ Channels Activating at Negative Voltages
Koschak, A., Reimer, D., Huber, I. G., Grabner, M., Glossmann, H. H., Engel, J., & Striessnig, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101469200 · Cited by 454
Splicing of α1A subunit gene generates phenotypic variants of P- and Q-type calcium channels
Bourinet, E., Soong, T. W., Sutton, K. G., Slaymaker, S., Mathews, E., Monteil, A., Zamponi, G. W., Nargeot, J., & Snutch, T. P. (1999) · Nature Neuroscience · doi:10.1038/8070 · Cited by 436
Structure of the Nav1.4-β1 Complex from Electric Eel
Zhen, Y., Zhou, Q., Wang, L., et al. (2017) · Cell · doi:10.1016/j.cell.2017.06.039 · Cited by 317
Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca2+ Channel
Zhao, Y., Huang, G., Wu, J., Wu, Q., Gao, S., Zhen, Y., Lei, J., & Yan, N. (2019) · Cell · doi:10.1016/j.cell.2019.04.043 · Cited by 258
The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels
Franckowiak, G., Bechem, M., Schramm, M., et al. (1985) · European Journal of Pharmacology · doi:10.1016/0014-2999(85)90631-4 · Cited by 249
Cellular Mechanisms of the Slow (<1 Hz) Oscillation in Thalamocortical Neurons In Vitro
Hughes, S. W., Cope, D. W., Blethyn, K. L., & Crunelli, V. (2002) · Neuron · doi:10.1016/s0896-6273(02)00623-2 · Cited by 243
T-Type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures
Tringham, E. W., Powell, K. L., Cain, S. M., Kuplast-Barr, K. G., Mezeyova, J., Weerapura, M., Eduljee, C., Jiang, X., Smith, P., Morrison, J.-L., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003120 · Cited by 224
Welling, A., Ludwig, A., Zimmer, S., et al. (1997) · Circulation Research · doi:10.1161/01.res.81.4.526 · Cited by 219
Williams, S. R., Toth, T. I., Turner, J. P., Hughes, S. W., & Crunelli, V. (1997) · The Journal of Physiology · doi:10.1111/j.1469-7793.1997.689ba.x · Cited by 219
Sinnegger-Brauns, M. J., Hetzenauer, A., Huber, I. G., Renström, E., Wietzorrek, G., Berjukow, S., Cavalli, M., Walter, D., Koschak, A., Waldschütz, R., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20208 · Cited by 215
Li, Y., Tatsui, C. E., Rhines, L. D., North, R. Y., Harrison, D. S., Cassidy, R. M., Johansson, C. A., Kosturakis, A. K., Edwards, D. D., Zhang, H., et al. (2016) · Pain · doi:10.1097/j.pain.0000000000000774 · Cited by 201
Role of voltage-gated L-type Ca2+ channel isoforms for brain function
Striessnig, J., Koschak, A., Sinnegger-Brauns, M. J., Hetzenauer, A., Nguyen, N. K., Busquet, P., Pelster, G., & Singewald, N. (2006) · Biochemical Society Transactions · doi:10.1042/bst0340903 · Cited by 183
Cryo-EM structures of apo and antagonist-bound human Cav3.1
Zhao, Y., Huang, G., Wu, Q., Wu, K. K., Li, R., Lei, J., Pan, X., & Yan, N. (2019) · Nature · doi:10.1038/s41586-019-1801-3 · Cited by 183
Singh, A., Gebhart, M., Fritsch, R., Sinnegger-Brauns, M. J., Poggiani, C., Hoda, J., Engel, J., Romanin, C., Striessnig, J., & Koschak, A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802254200 · Cited by 169
Structures of closed and open states of a voltage-gated sodium channel
Lenaeus, M. J., El-Din, T. M. G., Ing, C. E., Ramanadane, K., Pomès, R., Zheng, N., & Catterall, W. A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700761114 · Cited by 166
Striessnig, J., Murphy, B. J., & Catterall, W. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.23.10769 · Cited by 146
Schlick, B., Flucher, B. E., & Obermair, G. J. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.02.037 · Cited by 144
Shipe, W. D., Barrow, J. C., Yang, Z.-Q., Lindsley, C. W., Yang, F., Schlegel, K.-A. S., Shu, Y., Rittle, K. E., Bock, M. G., Hartman, G. D., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800419w · Cited by 143
Ethosuximide: From Bench to Bedside
Gören, M. Z., & Onat, F. (2007) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2007.00009.x · Cited by 132
Hemara‐Wahanui, A., Berjukow, S., Hope, C., Dearden, P. K., Wu, S., Wilson-Wheeler, J. C., Sharp, D. M., Lundon-Treweek, P., Clover, G. M., Hoda, J., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501907102 · Cited by 132
Schuster, A., Lacinová, Ľ., Klugbauer, N., Ito, H., Birnbaumer, L., & Hofmann, F. B. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00592.x · Cited by 123
Molecular Determinants of High Affinity Dihydropyridine Binding in L-type Calcium Channels
Peterson, B. Z., Tanada, T. N., & Catterall, W. A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.10.5293 · Cited by 119
Furukawa, T., Yamakawa, T., Midera, T., Sagawa, T., Mori, Y., & Nukada, T. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)35127-4 · Cited by 116
Koschak, A., Reimer, D., Walter, D., Hoda, J., Heinzle, T., Grabner, M., & Striessnig, J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-14-06041.2003 · Cited by 108
Park, H., Zhou, G., Baek, M., Baker, D. A., & DiMaio, F. (2021) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.0c01184 · Cited by 105
Xiang, Z., Thompson, A. D., Brogan, J. T., Schulte, M. I., Melancon, B. J., Mi, D., Lewis, L. M., Zou, B., Yang, L., Morrison, R. D., et al. (2011) · ACS Chemical Neuroscience · doi:10.1021/cn200090z · Cited by 98
Peterson, B. Z., Johnson, B. D., Hockerman, G. H., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.30.18752 · Cited by 97
Genetic T-type calcium channelopathies
Weiss, N., & Zamponi, G. W. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2019-106163 · Cited by 91
Perez‐Reyes, E., Deusen, A. L. V., & Vitko, I. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.145672 · Cited by 89
Mitterdorfer, J., Wang, Z., Sinnegger, M. J., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.48.30330 · Cited by 86
Hockerman, G. H., Peterson, B. Z., Sharp, E. M., Tanada, T. N., Scheuer, T., & Catterall, W. A. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.26.14906 · Cited by 85
EMC chaperone–CaV structure reveals an ion channel assembly intermediate
Chen, Z., Mondal, A., Abderemane-Ali, F., Jang, S., Niranjan, S., Montaño, J. L., Zaro, B. W., & Minor, D. L. (2023) · Nature · doi:10.1038/s41586-023-06175-5 · Cited by 81
Yamaguchi, S., Okamura, Y., Nagao, T., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m007165200 · Cited by 78
Sinnegger, M. J., Wang, Z., Grabner, M., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.27686 · Cited by 73
Characterization of Cav1.4 Complexes (α11.4, β2, and α2δ4) in HEK293T Cells and in the Retina
Lee, A., Wang, S., Williams, B., Hagen, J., Scheetz, T. E., & Haeseleer, F. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.607465 · Cited by 66
Self-citationZ944: A first in class T‐type calcium channel modulator for the treatment of pain
Lee, M. (2014) · Journal of the Peripheral Nervous System · doi:10.1111/jns.12080_2 · Cited by 64
The T‐type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity
Harding, E. K., Dedek, A., Bonin, R. P., Salter, M. W., Snutch, T. P., & Hildebrand, M. E. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15498 · Cited by 53
Furukawa, T., Nukada, T., Namiki, Y., et al. (2009) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2009.04.036 · Cited by 51
Huang, H. Y., Yu, D., & Soong, T. W. (2013) · Molecular Pharmacology · doi:10.1124/mol.113.087155 · Cited by 50
Molecular Mechanism of Calcium Channel Block by Isradipine
Berjukow, S., Marksteiner, R., Gapp, F., et al. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m908836199 · Cited by 50
T-Type Channel Druggability at a Crossroads
Weiss, N., & Zamponi, G. W. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00031 · Cited by 39
Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina
Haeseleer, F., Williams, B., & Lee, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.731737 · Cited by 36
Self-citationStructural bases of inhibitory mechanism of CaV1.2 channel inhibitors
Wei, Y., Yu, Z., Wang, L., Li, X., Li, N., Bai, Q., Wang, Y., Li, R., Meng, Y., Xu, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47116-8 · Cited by 36
Role of L-type Ca2+channel isoforms in the extinction of conditioned fearPreprint
Busquet, P., Hetzenauer, A., Sinnegger-Brauns, M. J., Striessnig, J., & Singewald, N. (2008) · Learning & Memory · doi:10.1101/lm.886208 · Cited by 36
A concerted action of L- and T-type Ca2+ channels regulates locus coeruleus pacemaking
Matschke, L. A., Bertoune, M., Roeper, J., Snutch, T. P., Oertel, W. H., Rinné, S., & Decher, N. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.08.012 · Cited by 35
Structural basis for human Cav3.2 inhibition by selective antagonists
Huang, J., Fan, X., Jin, X., Lyu, C., Guo, Q., Liu, T., Chen, J., Davakan, A., Lory, P., & Yan, N. (2024) · Cell Research · doi:10.1038/s41422-024-00959-8 · Cited by 34
T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease
Matthews, L. G., Puryear, C. B., Correia, S. S., Srinivasan, S. R., Belfort, G. M., Pan, M., & Kuo, S. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51735 · Cited by 30
Calcium Channels in Retinal Function and Disease
Williams, B., Maddox, J. W., & Lee, A. (2022) · Annual Review of Vision Science · doi:10.1146/annurev-vision-012121-111325 · Cited by 29
Self-citationWang, Y., Tang, S., Harvey, K. E., et al. (2018) · Molecular Pharmacology · doi:10.1124/mol.118.112441 · Cited by 22
Noradrenaline upregulates T‐type calcium channels in rat pinealocytes
Yu, H., Seo, J. B., Jung, S., Koh, D., & Hille, B. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.284208 · Cited by 20
Cav1.3‐selective inhibitors of voltage‐gated L‐type Ca2+ channels: Fact or (still) fiction?
Filippini, L., Ortner, N. J., Kaserer, T., et al. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16060 · Cited by 17
Scott, L., Puryear, C. B., Belfort, G. M., Raines, S. R., Hughes, Z. A., Matthews, L. G., Ravina, B. M., & Wittmann, M. (2022) · Movement Disorders · doi:10.1002/mds.28969 · Cited by 17
Wang, X., Du, L., & Peterson, B. Z. (2007) · Biochemistry · doi:10.1021/bi7001696 · Cited by 15
Williams, B., Haeseleer, F., & Lee, A. (2018) · The Journal of General Physiology · doi:10.1085/jgp.201812140 · Cited by 14
Self-citationMeasuring Ca2+-Dependent Modulation of Voltage-Gated Ca2+ Channels in HEK-293T CellsPreprint
Thomas, J. R., & Lee, A. (2016) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot087213 · Cited by 14
Self-citationT-Type Ca2+ Channels Boost Neurotransmission in Mammalian Cone Photoreceptors
Davison, A., Lux, U. T., Brandstätter, J. H., et al. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1878-21.2022 · Cited by 13
Galván, A., Devergnas, A. D., Pittard, D., et al. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00186 · Cited by 10
Roebuck, A. J., Marks, W. N., Liu, M. C., Tahir, N. B., Zabder, N. K., Snutch, T. P., & Howland, J. G. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5040-3 · Cited by 10
Baggio, D. F., Gambeta, E., Souza, I. A., Huang, S., Zamponi, G. W., & Chichorro, J. G. (2024) · The Journal of Headache and Pain · doi:10.1186/s10194-024-01921-0 · Cited by 8
Maddox, J. W., Ordemann, G. J., Vázquez, J. A. D. L. R., et al. (2024) · eLife · doi:10.7554/elife.94908 · Cited by 7
Self-citationEthosuximide: Subunit‐ and Gβγ‐dependent blocker and reporter of allosteric changes in GIRK channels
Shalomov, B., Friesacher, T., Yakubovich, D., Combista, J. C., Reddy, H. P., Dabbah, S., Bernsteiner, H., Zangerl‐Plessl, E., Stary‐Weinzinger, A., & Dascal, N. (2025) · British Journal of Pharmacology · doi:10.1111/bph.17446 · Cited by 6
Calcium Channels in Retinal Function and DiseasePreprint
Williams, B., Maddox, W., & Lee, A. (2021) · Preprints.org · doi:10.20944/preprints202101.0466.v1 · Cited by 5
Self-citationGündüz, M. G., Dengiz, C., Denzinger, K., et al. (2025) · Archiv der Pharmazie · doi:10.1002/ardp.202400584 · Cited by 3
Giroux, M., Zhao, J., Jacotin, H., et al. (2024) · Neurology · doi:10.1212/wnl.0000000000206620 · Cited by 3
Maddox, J. W., Ordemann, G. J., Vázquez, J. D. L. R., et al. (2024) · eLife · doi:10.7554/elife.94908.4 · Cited by 3
Self-citation
Flagged first, then by citations
Metadata
- Authors
- Sun, J., de la Rosa Vázquez, J., Hernández-González, A., Yarov-Yarovoy, V., & Lee, A.
- Affiliations
- The University of Texas at Austin (US)
- The University of Texas at Austin 1 Department of Neuroscience and Center for Learning and Memory, , Austin, TX,
- University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,
- University of California, Davis (US)
- Corresponding author
- Lee, Amy
- ORCID
- Venue
- Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 2026-01-05
- Volume
- 158
- Issue
- 2
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC13080778
- OpenAlex
- W7118383914
- Cited by
- 0
- References
- 73
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- The Journal of General Physiology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (R01 EY026817, R03TR005086, R01HL174001)
- Karl Folkers Chair in Interdisciplinary Biomedical Research
- 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 › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- off-target inhibition, structure-based modeling
- MeSH terms
- Animals, Calcium Channel Blockers, Humans, Calcium Channels, T-Type, Caveolin 3, HEK293 Cells
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
