ABSTRACT
The turripeptide ubi3a was isolated from the venom of the marine gastropod Unedogemmula bisaya, family Turridae, by bioassay-guided purification; both native and synthetic ubi3a elicited prolonged tremors when injected intracranially into mice. The sequence of the peptide, DCCOCOAGAVRCRFACC-NH2 (O = 4-hydroxyproline) follows the framework III pattern for cysteines (CC-C-C-CC) in the M-superfamily of conopeptides. The three-dimensional structure determined by NMR spectroscopy indicated a disulfide connectivity that is not found in conopeptides with the cysteine framework III: C1-C4, C2-C6, C3-C5. The peptide inhibited the activity of the α9α10 nicotinic acetylcholine receptor with relatively low affinity (IC50, 10.2 µM). Initial Constellation Pharmacology data revealed an excitatory activity of ubi3a on a specific subset of mouse dorsal root ganglion neurons.
Subject(s)
Conotoxins/chemistry , Conotoxins/pharmacology , Conus Snail/chemistry , Animals , Calcium/metabolism , Cells, Cultured , Conotoxins/isolation & purification , Conus Snail/drug effects , Conus Snail/genetics , Conus Snail/growth & development , Female , Ganglia, Spinal/cytology , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Male , Mice , Mice, Inbred ICR , Models, Molecular , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Oocytes/cytology , Oocytes/drug effects , Oocytes/metabolism , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Receptors, Nicotinic/metabolism , Xenopus laevisABSTRACT
Imposex is a reproductive abnormality in which female snails begin to transform to males, but do not become functional. It was caused by tributyltin (TBT) used as an antifoulant in boat paints. Imposex was first recorded marine snails (Conus) (Mollusca: Caenogastropoda) at Rottnest Island, Western Australia, in January 1991, where 88% of individuals at the west end were affected. Most were at moderate Stages 3 and 4 on a scale of 0 (no affect) to 6 (death). TBT was banned on boats <25m long in late 1991 in WA. In 1996, imposex had declined to 69% of females with Stages 3 and 4 still the most common. By 2007 only 35% of females exhibited imposex; Stage 3 was the highest level recorded. TBT was below detection limits. TBT was banned on vessels >25m in September 2013. In February 2017 only 4% of Conus had imposex, at Stage 1.
Subject(s)
Conus Snail/drug effects , Disorders of Sex Development/chemically induced , Trialkyltin Compounds/toxicity , Water Pollutants, Chemical/toxicity , Animals , Disorders of Sex Development/veterinary , Environmental Monitoring , Female , Male , Paint , Ships , Western AustraliaABSTRACT
Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: µ-, µO-, δ- and ί-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the µ- and µO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the µ- and µO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed.