{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:05:32Z","timestamp":1789682732808,"version":"4.0.1"},"reference-count":62,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council of Research and Development, the Ministry of Science, Technology (CNPq), and Innovation (MCTI), the Federal Government of Brazil, Bras\u00edlia, DF, Brazil","award":["CNPq #305316\/2021-4"],"award-info":[{"award-number":["CNPq #305316\/2021-4"]}]},{"name":"National Council of Research and Development, the Ministry of Science, Technology (CNPq), and Innovation (MCTI), the Federal Government of Brazil, Bras\u00edlia, DF, Brazil","award":["CNPq # 401900\/2022-3"],"award-info":[{"award-number":["CNPq # 401900\/2022-3"]}]},{"name":"Ministry of Science, Innovation and Universities (MICIU), Madrid, Spain","award":["PID2021-128133NB-I00\/AEI\/FEDER10.13039\/501100011033"],"award-info":[{"award-number":["PID2021-128133NB-I00\/AEI\/FEDER10.13039\/501100011033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: One of the neurotoxic components from the sea trumpet polyps, Protopalythoa variabilis (Cnidaria, Anthozoa), is a 26-residue, V-shape helical peptide (PpV\u03b1). Its synthetic versions, i.e., the linear, the single-disulfide-bonded analog, and the chimeric peptide with a 6-residue stretch of the N-terminal native homologous peptide covalently linked to the linear sequence, were investigated for their activity on ion channels responsible for cellular excitability and synaptic transmission. Methods: Molecular docking analyses and dynamic simulations focused on the ability of PpV\u03b1 peptides to bind ion channels selectively through interaction with critical residues at their binding sites. Results: Electrophysiological studies using the patch clamp technique with sympathetic bovine chromaffin cells from the adrenal medulla confirmed that PpV\u03b1 analogs can block both sodium and calcium currents, which are responsible for initiating and propagating action potentials, respectively, and for neurotransmitter release. Additionally, the peptides displayed neuroprotective effects, attenuating cellular damage induced by veratridine, which interferes with sodium channel activity, and by oligomycin and rotenone (O\/R), which affect mitochondrial function. Conclusions: The block of calcium and sodium channels and the neuroprotective effects against oxidative stress make the PpV\u03b1 peptide scaffold an attractive template for developing agents that has significant clinical potential in several areas, such as the treatment of neurological diseases (epilepsy, multiple sclerosis, and neurodegenerative diseases), neuroprotection in acute events (stroke and traumatic brain or spinal cord injuries), the management of neuropathic pain, the prevention of ischemic damage, and psychiatric disorders (anxiety and bipolar disorder).<\/jats:p>","DOI":"10.3390\/ph18111701","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:35:31Z","timestamp":1762770931000},"page":"1701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibitory Activity of Calcium and Sodium Ion Channels of Neurotoxic Protoplaythoa variabilis V-Shape Helical Peptide Analogs and Their Neuroprotective Effect In Vitro"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6465-1107","authenticated-orcid":false,"given":"Ariane","family":"Teixeira dos Santos","sequence":"first","affiliation":[{"name":"Graduate Program in Pharmaceutical Sciences, Faculty of Pharmacy, Dentistry and Nursing, Federal University of Cear\u00e1, Fortaleza 60430-370, Ceara, Brazil"},{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Jim\u00e9nez Carretero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Hern\u00e1ndez Campano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-6097","authenticated-orcid":false,"given":"Ricardo","family":"de Pascual","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon Ming-Yuen","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8950-0033","authenticated-orcid":false,"given":"Clarence Tsun Ting","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9210-092X","authenticated-orcid":false,"given":"Gandhi","family":"R\u00e1dis-Baptista","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Biotechnology, Institute for Marine Sciences, Federal University of Cear\u00e1, Fortaleza 60430-370, Ceara, Brazil"},{"name":"Department of Biochemistry and Biophysics, Institute for Health Sciences, Federal University of Bahia, Salvador 40231-300, Bahia, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-5351","authenticated-orcid":false,"given":"Jes\u00fas Miguel","family":"Hern\u00e1ndez-Guijo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"},{"name":"Ram\u00f3n y Cajal Institute for Health Research, IRYCIS, Hospital Ram\u00f3n y Cajal, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.semcdb.2017.07.026","article-title":"Pore-Forming Toxins in Cnidaria","volume":"72","author":"Podobnik","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.bbamem.2015.09.007","article-title":"Pore Formation by Actinoporins, Cytolysins from Sea Anemones","volume":"1858","author":"Rojko","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3390\/md403070","article-title":"Cnidarian Toxins Acting on Voltage-Gated Ion Channels","volume":"4","author":"Messerli","year":"2006","journal-title":"Mar. Drugs"},{"key":"ref_4","unstructured":"Thorp, J.H., and Rogers, D.C. (2015). Chapter 9\u2014Phylum Cnidaria. Thorp and Covich\u2019s Freshwater Invertebrates, Academic Press. [4th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1387\/ijdb.113472ab","article-title":"The Nematocyst: A Molecular Map of the Cnidarian Stinging Organelle","volume":"56","author":"Beckmann","year":"2012","journal-title":"Int. J. Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"74","DOI":"10.2174\/1871524915666150309141900","article-title":"Neurotoxic and Neuroactive Compounds from Cnidaria: Five Decades of Research\u2026.and More","volume":"15","author":"Mariottini","year":"2015","journal-title":"Cent. Nerv. Syst. Agents Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Monastyrnaya, M.M., Kalina, R.S., and Kozlovskaya, E.P. (2022). The Sea Anemone Neurotoxins Modulating Sodium Channels: An Insight at Structure and Functional Activity after Four Decades of Investigation. Toxins, 15.","DOI":"10.3390\/toxins15010008"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Prentis, P.J., Pavasovic, A., and Norton, R.S. (2018). Sea Anemones: Quiet Achievers in the Field of Peptide Toxins. Toxins, 10.","DOI":"10.3390\/toxins10010036"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.toxicon.2011.07.016","article-title":"Development of a Sea Anemone Toxin as an Immunomodulator for Therapy of Autoimmune Diseases","volume":"59","author":"Chi","year":"2012","journal-title":"Toxicon"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Tajti, G., Wai, D.C.C., Panyi, G., and Norton, R.S. (2020). The Voltage-Gated Potassium Channel KV1.3 as a Therapeutic Target for Venom-Derived Peptides. Biochem. Pharmacol., 181.","DOI":"10.1016\/j.bcp.2020.114146"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"D\u2019Ambra, I., and Lauritano, C. (2020). A Review of Toxins from Cnidaria. Mar. Drugs, 18.","DOI":"10.3390\/md18100507"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Klompen, A.M.L., Kayal, E., Collins, A.G., and Cartwright, P. (2021). Phylogenetic and Selection Analysis of an Expanded Family of Putatively Pore-Forming Jellyfish Toxins (Cnidaria: Medusozoa). Genome Biol. Evol., 13.","DOI":"10.1093\/gbe\/evab081"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Li, R., Yu, H., Li, A., Yu, C., and Li, P. (2023). Identification and Characterization of the Key Lethal Toxin from Jellyfish Cyanea Nozakii. Int. J. Biol. Macromol, 230.","DOI":"10.1016\/j.ijbiomac.2023.123176"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00204-018-2334-5","article-title":"Novel Neurotoxic Peptides from Protopalythoa variabilis Virtually Interact with Voltage-gated Sodium Channel and Display Anti-epilepsy and Neuroprotective Activities in Zebrafish","volume":"93","author":"Liao","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Macrander, J., Brugler, M.R., and Daly, M. (2015). A RNA-Seq Approach to Identify Putative Toxins from Acrorhagi in Aggressive and Non-Aggressive Anthopleura Elegantissima Polyps. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1417-4"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ram\u00edrez-Carreto, S., Vera-Estrella, R., Portillo-Bobadilla, T., Licea-Navarro, A., Bernaldez-Sarabia, J., Rudi\u00f1o-Pi\u00f1era, E., Verleyen, J.J., Rodr\u00edguez, E., and Rodr\u00edguez-Almaz\u00e1n, C. (2019). Transcriptomic and Proteomic Analysis of the Tentacles and Mucus of Anthopleura Dowii Verrill, 1869. Mar. Drugs, 17.","DOI":"10.3390\/md17080436"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1093\/gbe\/evw204","article-title":"The Transcriptome of the Zoanthid Protopalythoa variabilis (Cnidaria, Anthozoa) Predicts a Basal Repertoire of Toxin-like and Venom-Auxiliary Polypeptides","volume":"8","author":"Huang","year":"2016","journal-title":"Genome Biol. Evol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lazcano-P\u00e9rez, F., Castro, H., Arenas, I., Garc\u00eda, D.E., Gonz\u00e1lez-Mu\u00f1oz, R., and Arregu\u00edn-Espinosa, R. (2016). Activity of Palythoa Caribaeorum Venom on Voltage-Gated Ion Channels in Mammalian Superior Cervical Ganglion Neurons. Toxins, 8.","DOI":"10.3390\/toxins8050135"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6215","DOI":"10.1021\/cr300444k","article-title":"Introduction to Ion Channels and Disease","volume":"112","author":"Kasianowicz","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/bs.apcsb.2015.10.006","article-title":"Ion Channels in Neurological Disorders","volume":"103","author":"Kumar","year":"2016","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lia, A., Di Spiezio, A., Vitalini, L., Tore, M., Puja, G., and Losi, G. (2023). Ion Channels and Ionotropic Receptors in Astrocytes: Physiological Functions and Alterations in Alzheimer\u2019s Disease and Glioblastoma. Life, 13.","DOI":"10.3390\/life13102038"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2174\/1871527315666160202125914","article-title":"Inflammatory Mechanisms and Oxidative Stress as Key Factors Responsible for Progression of Neurodegeneration: Role of Brain Innate Immune System","volume":"15","author":"Leszek","year":"2016","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lamptey, R.N.L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., and Singh, J. (2022). A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics. Int. J. Mol. Sci, 23.","DOI":"10.3390\/ijms23031851"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.cell.2019.01.047","article-title":"Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin","volume":"176","author":"Xu","year":"2019","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"109931","DOI":"10.1016\/j.celrep.2021.109931","article-title":"Closed-State Inactivation and Pore-Blocker Modulation Mechanisms of Human CaV2.2","volume":"37","author":"Dong","year":"2021","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4091","DOI":"10.1021\/acs.jmedchem.9b00141","article-title":"Structure- and Ligand-Based Discovery of Chromane Arylsulfonamide Nav1.7 Inhibitors for the Treatment of Chronic Pain","volume":"62","author":"McKerrall","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1039\/C5NP00156K","article-title":"Marine Natural Products","volume":"33","author":"Blunt","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4006","DOI":"10.3390\/md13074006","article-title":"Marine Peptides: Bioactivities and Applications","volume":"13","author":"Cheung","year":"2015","journal-title":"Mar. Drugs"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bbagen.2017.08.014","article-title":"Marine Natural Product Peptides with Therapeutic Potential: Chemistry, Biosynthesis, and Pharmacology","volume":"1862","author":"Gogineni","year":"2018","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Madio, B., King, G.F., and Undheim, E.A.B. (2019). Sea Anemone Toxins: A Structural Overview. Mar. Drugs, 17.","DOI":"10.3390\/md17060325"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Margiotta, F., Micheli, L., Ciampi, C., Ghelardini, C., McIntosh, J.M., and Di Cesare Mannelli, L. (2022). Conus Regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism. Mar. Drugs, 20.","DOI":"10.3390\/md20120773"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jprot.2017.07.007","article-title":"Revisiting Venom of the Sea Anemone Stichodactyla Haddoni: Omics Techniques Reveal the Complete Toxin Arsenal of a Well-Studied Sea Anemone Genus","volume":"166","author":"Madio","year":"2017","journal-title":"J. Proteom."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.3390\/md11093335","article-title":"Pharmacological Studies of Tentacle Extract from the Jellyfish Cyanea Capillata in Isolated Rat Aorta","volume":"11","author":"Wang","year":"2013","journal-title":"Mar. Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0167-4838(99)00165-X","article-title":"Role of Disulfide Bridges in the Folding, Structure and Biological Activity of Omega-Conotoxin GVIA","volume":"1434","author":"Flinn","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.4155\/fmc.14.93","article-title":"The Role of Disulfide Bonds in Structure and Activity of Chlorotoxin","volume":"6","author":"Ojeda","year":"2014","journal-title":"Future Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13063","DOI":"10.1021\/jacs.7b06506","article-title":"The Role of Disulfide Bond Replacements in Analogues of the Tarantula Toxin ProTx-II and Their Effects on Inhibition of the Voltage-Gated Sodium Ion Channel Nav1.7","volume":"139","author":"Wright","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1113\/jphysiol.1976.sp011618","article-title":"Electrical Excitability of Cultured Adrenal Chromaffin Cells","volume":"262","author":"Biales","year":"1976","journal-title":"J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.ydbio.2006.07.010","article-title":"The Sympathoadrenal Cell Lineage: Specification, Diversification, and New Perspectives","volume":"298","author":"Huber","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1111\/j.1749-6632.2002.tb04498.x","article-title":"Chromaffin Cells as Models of Endocrine Cells and Neurons","volume":"971","author":"Tischler","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","article-title":"A Quantitative Description of Membrane Current and Its Application to Conduction and Excitation in Nerve","volume":"117","author":"Hodgkin","year":"1952","journal-title":"J. Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nrn1516","article-title":"Ca(2+)-Activated K+ Channels: Molecular Determinants and Function of the SK Family","volume":"5","author":"Stocker","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1016\/j.bpj.2009.06.042","article-title":"Differential Regulation of Action Potentials by Inactivating and Noninactivating BK Channels in Rat Adrenal Chromaffin Cells","volume":"97","author":"Sun","year":"2009","journal-title":"Biophys. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1113\/jphysiol.1968.sp008469","article-title":"The Role of Calcium in Neuromuscular Facilitation","volume":"195","author":"Katz","year":"1968","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/366156a0","article-title":"Different Types of Calcium Channels Mediate Central Synaptic Transmission","volume":"366","author":"Takahashi","year":"1993","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.ceca.2007.04.015","article-title":"L-Type Calcium Channels in Adrenal Chromaffin Cells: Role in Pace-Making and Secretion","volume":"42","author":"Marcantoni","year":"2007","journal-title":"Cell Calcium"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"C610","DOI":"10.1152\/ajpcell.00380.2010","article-title":"Modulation by Endogenously Released ATP and Opioids of Chromaffin Cell Calcium Channels in Mouse Adrenal Slices","volume":"300","year":"2011","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4017","DOI":"10.1046\/j.1460-9568.2000.00305.x","article-title":"BDNF, NT-3 and NGF Induce Distinct New Ca2+ Channel Synthesis in Developing Hippocampal Neurons","volume":"12","author":"Baldelli","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1523\/JNEUROSCI.4961-09.2010","article-title":"Loss of Cav1.3 Channels Reveals the Critical Role of L-Type and BK Channel Coupling in Pacemaking Mouse Adrenal Chromaffin Cells","volume":"30","author":"Marcantoni","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1002\/j.2040-4603.2019.tb00098.x","article-title":"Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease","volume":"9","author":"Carbone","year":"2019","journal-title":"Compr. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1152\/physrev.00039.2005","article-title":"Calcium Signaling and Exocytosis in Adrenal Chromaffin Cells","volume":"86","author":"Borges","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.1748-1716.2007.01815.x","article-title":"Calcium Channels in Chromaffin Cells: Focus on L and T Types","volume":"192","author":"Marcantoni","year":"2008","journal-title":"Acta Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1126\/science.7716515","article-title":"Calcium Signaling in Neurons: Molecular Mechanisms and Cellular Consequences","volume":"268","author":"Ghosh","year":"1995","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.drudis.2018.08.011","article-title":"Cnidarian Peptide Neurotoxins: A New Source of Various Ion Channel Modulators or Blockers against Central Nervous Systems Disease","volume":"24","author":"Liao","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1124\/jpet.109.154765","article-title":"Mitochondrial Na+\/Ca2+-Exchanger Blocker CGP37157 Protects against Chromaffin Cell Death Elicited by Veratridine","volume":"330","author":"Nicolau","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.toxicon.2004.01.012","article-title":"Veratridine Modifies the TTX-Resistant Na+ Channels in Rat Vagal Afferent Neurons","volume":"43","author":"Campos","year":"2004","journal-title":"Toxicon"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A Web-Based Graphical User Interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1021\/acs.jctc.5b00935","article-title":"CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM Simulations Using the CHARMM36 Additive Force Field","volume":"12","author":"Lee","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1007\/s00204-022-03311-4","article-title":"Anti-epileptic Kunitz-like Peptides Discovered in the Branching Coral Acropora Digitifera through Transcriptomic Analysis","volume":"96","author":"Chen","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00424-017-2048-1","article-title":"Roles of Na+, Ca2+, and K+ Channels in the Generation of Repetitive Firing and Rhythmic Bursting in Adrenal Chromaffin Cells","volume":"470","author":"Lingle","year":"2018","journal-title":"Pflugers Arch."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1002\/iub.2117","article-title":"Cholinergic and Peptidergic Neurotransmission in the Adrenal Medulla: A Dynamic Control of Stimulus-Secretion Coupling","volume":"72","year":"2020","journal-title":"IUBMB Life"},{"key":"ref_62","first-page":"3751","article-title":"Multiple Neurotransmitter Synthesis by Human Neuroblastoma Cell Lines and Clones","volume":"38","author":"Biedler","year":"1978","journal-title":"Cancer Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1701\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T10:40:58Z","timestamp":1762771258000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/11\/1701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,10]]},"references-count":62,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ph18111701"],"URL":"https:\/\/doi.org\/10.3390\/ph18111701","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,10]]}}}