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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 \u03b22x13 and \u03b12\u03b4-4 subunits, Z944 and ML218 inhibited Ca2+ currents with IC50 values of \u223c30 and 2 \u00b5M, 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 \u223c37 \u00b5M) 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.<\/jats:p>","DOI":"10.1085\/jgp.202513879","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T07:20:38Z","timestamp":1765524038000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of CaV1.4 channels by CaV3 channel antagonists ML218 and Z944"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3404-5353","authenticated-orcid":true,"given":"Jinglang","family":"Sun","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 Department of Neuroscience and Center for Learning and Memory, , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6266-5919","authenticated-orcid":true,"given":"Juan","family":"de la Rosa V\u00e1zquez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 Department of Neuroscience and Center for Learning and Memory, , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3235-442X","authenticated-orcid":true,"given":"Adriana","family":"Hern\u00e1ndez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05rrcem69","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-4834","authenticated-orcid":true,"given":"Vladimir","family":"Yarov-Yarovoy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05rrcem69","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/05rrcem69","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 3 Department of Anesthesiology and Pain Medicine, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8021-0443","authenticated-orcid":true,"given":"Amy","family":"Lee","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 Department of Neuroscience and Center for Learning and Memory, , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"key":"2026010509120455000_bib1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s10194-024-01921-0","article-title":"CaV3.2 T-type calcium channels contribute to CGRP-induced allodynia in a rodent model of experimental migraine","volume":"25","author":"Baggio","year":"2024","journal-title":"J. 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