ArticleMolecular brain2014
Block of T-type calcium channels by protoxins I and II.
Article in Molecular brain, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 47 citations in OpenAlex.
- Web of Potentials: Neuroactive Components of Spider Venom and Their Emerging Pharmacologic Applications in Neurologic Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Ion Channel-Targeting Toxins: Structural Mechanisms of Activation, Inhibition, and Therapeutic Potential.Toxins · 2025Review
- Article
- Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- ω-Grammotoxin-SIA inhibits voltage-gated Na+ channel currents.The Journal of general physiology · 2024Article
- Characterization of human iPSC-derived sensory neurons and their functional assessment using multi electrode array.Scientific reports · 2024Article
- Extracellular vesicles for developing targeted hearing loss therapy.Journal of controlled release : official journal of the Controlled Release Society · 2024Review
- Current Drug Development Overview: Targeting Voltage-Gated Calcium Channels for the Treatment of Pain.International journal of molecular sciences · 2023Review
- Computational design of peptides to target NaeLife · 2022Article
- T-Type Calcium Channels: A Mixed Blessing.International journal of molecular sciences · 2022Review
- µ-Theraphotoxin Pn3a inhibition of CaeLife · 2022Article
- Novel Fluorescence-Based High-Throughput FLIPR Assay Utilizing Membrane-Tethered Genetic Calcium Sensors to Identify T-Type Calcium Channel Modulators.ACS pharmacology & translational science · 2022Article
- Cyclic Peptides as T-Type Calcium Channel Blockers: Characterization and Molecular Mapping of the Binding Site.ACS pharmacology & translational science · 2021Article
- Pain-related toxins in scorpion and spider venoms: a face to face with ion channels.The journal of venomous animals and toxins including tropical diseases · 2021Review
- Engineering of a Spider PeptideFrontiers in molecular biosciences · 2021Article
- Venom-Derived Peptides Inhibiting Voltage-Gated Sodium and Calcium Channels in Mammalian Sensory Neurons.Advances in experimental medicine and biology · 2021Article
- Characterisation of d-Conotoxin TxVIA as a Mammalian T-Type Calcium Channel Modulator.Marine drugs · 2020Article
- Cochlear protein biomarkers as potential sites for targeted inner ear drug delivery.Drug delivery and translational research · 2020Review
- Spider Venom Peptide Pn3a Inhibition of Primary Afferent High Voltage-Activated Calcium Channels.Frontiers in pharmacology · 2020Article
- Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaJournal of medicinal chemistry · 2019Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundLow-voltage-activated (T-type) calcium channels play a crucial role in a number of physiological processes, including neuronal and cardiac pacemaker activity and nociception. Therefore, finding specific modulators and/or blockers of T-type channels has become an important field of drug discovery. One characteristic of T-type calcium channels is that they share several structural similarities with voltage-gated sodium channels (VGSCs). We therefore hypothesized that binding sites for certain sodium channel blocking peptide toxins may be present in T-type calcium channels.
findingsThe sodium channel blocker ProTx I tonically blocked native and transiently expressed T-type channels in the sub- to low micro molar range with at least a ten-fold selectivity for the T-type calcium channel hCav3.1 over hCav3.3, and more than one hundred fold selectivity over hCav3.2. Using chimeras of hCav3.1 and hCav3.3, we determined that the domain IV region of hCav3.1 is a major determinant of toxin affinity, with a minor contribution from domain II. Further analysis revealed several residues in a highly conserved region between T-type and sodium channels that may correspond to toxin binding sites. Mutagenesis of several of these residues on an individual basis, however, did not alter the blocking effects of the toxin. ProTx II on the other hand preferentially blocked hCav3.2 and significantly shifted the steady state inactivation of this channel.
conclusionsProTx I blocks hCav3.1 both selectively and with high affinity. Domain IV appears to play a major role in this selectivity with some contribution from domain II. Given the structural similarities between sodium and T-type calcium channels and the apparent conservation in toxin binding sites, these data could provide insights into the development and synthesis of novel T-type channel antagonists.
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