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TRPA1 is a chemosensory ion channel that functions as a sentinel for structurally diverse electrophilic irritants. Channel activation occurs through an unusual mechanism involving covalent modification of cysteine residues clustered within an amino-terminal cytoplasmic domain. Here, we describe a peptidergic scorpion toxin (WaTx) that activates TRPA1 by penetrating the plasma membrane to access the same intracellular site modified by reactive electrophiles. WaTx stabilizes TRPA1 in a biophysically distinct active state characterized by prolonged channel openings and low Ca2+ permeability. Consequently, WaTx elicits acute pain and pain hypersensitivity but fails to trigger efferent release of neuropeptides and neurogenic inflammation typically produced by noxious electrophiles. These findings provide a striking example of convergent evolution whereby chemically disparate animal- and plant-derived irritants target the same key allosteric regulatory site to differentially modulate channel activity. WaTx is a unique pharmacological probe for dissecting TRPA1 function and its contribution to acute and persistent pain.

ABSTRACT Venom represents a key adaptation of many venomous predators, allowing them to immobilise prey quickly through chemical rather than physical warfare. Evolutionary arms races between prey and a predator are believed to be the main factor influencing the potency and composition of predatory venoms. Predators with narrowly restricted diets are expected to evolve specifically potent venom towards their focal prey, with lower efficacy on alternative prey. Here, we evaluate hypotheses on the evolution of prey‐specific venom, focusing on the effect of restricted diet, prey defences, and prey resistance. Prey specificity as a potential evolutionary dead end is also discussed. We then provide an overview of the current knowledge on venom prey specificity, with emphasis on snakes, cone snails, and spiders. As the current evidence for venom prey specificity is still quite limited, we also overview the best approaches and methods for its investigation and provide a brief summary of potential model groups. Finally, possible applications of prey‐specific toxins are discussed. [ABSTRACT FROM AUTHOR]

Molecular imaging has revolutionised the field of biomedical research by providing a non-invasive means to visualise and understand biochemical processes within living organisms. Optical fluorescent imaging in particular allows researchers to gain valuable insights into the dynamic behaviour of a target of interest in real time. Ion channels play a fundamental role in cellular signalling, and they are implicated in diverse pathological conditions, making them an attractive target in the field of molecular imaging. Many venom peptides exhibit exquisite selectivity and potency towards ion channels, rendering them ideal agents for molecular imaging applications. In this review, we illustrate the use of fluorescently-labelled venom peptides for disease diagnostics and intraoperative imaging of brain tumours and peripheral nerves. Finally, we address challenges for the development and clinical translation of venom peptides as nerve-targeted imaging agents. [ABSTRACT FROM AUTHOR]

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

The article discusses the potential benefits of blocking acid-sensing ion channel 1a (ASIC1a) in reducing myocardial injury in rodent models of myocardial infarction (MI). The study found that administering the ASIC1a inhibitor, Hi1a, before or after the onset of ischemia reduced infarct size and prevented cardiac dysfunction associated with MI. Hi1a was also found to have minimal adverse effects on heart rhythm and blood pressure. The findings suggest that Hi1a could be a promising drug candidate for treating severe ischemic injury in patients with MI. Further research is needed to evaluate Hi1a in larger animal models and in co-morbid conditions to assess its potential for clinical translation. [Extracted from the article]

The sweet potato whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) is responsible for significant crop losses and presents one of the greatest challenges for global agricultural pest management. Management of whitefly populations and associated plant viral diseases is hindered by widespread whitefly resistance to chemical insecticides. An alternative control approach involves the use of insect‐specific neurotoxins, but these require delivery from the whitefly gut into the haemocoel. Here we demonstrate that the coat protein (CP) of a begomovirus, Tomato yellow leaf curl virus, is sufficient for delivery of fused proteins into the whitefly haemocoel without virion assembly. Following feeding on the recombinant CP‐P‐mCherry fusion (where ‐P‐ is a proline‐rich linker), mCherry fluorescence was detected in the dorsal aorta and pericardial cells of the whitefly, but not in those of whitefly fed on negative control treatments, indicating effective CP‐mediated delivery of mCherry into the whitefly haemocoel. Significant mortality was observed in whiteflies fed on a fusion of CP‐P to the insect‐specific neurotoxin Hv1a, but not in whiteflies fed on CP‐P fused to a disarmed Hv1a mutant. Begomovirus coat protein – insect neurotoxin fusions hold considerable potential for transgenic resistance to whitefly providing valuable tools for whitefly management. [ABSTRACT FROM AUTHOR]

The piercing-sucking mouthparts of the true bugs (Insecta: Hemiptera: Heteroptera) have allowed diversification from a plant-feeding ancestor into a wide range of trophic strategies that include predation and blood-feeding. Crucial to the success of each of these strategies is the injection of venom. Here we review the current state of knowledge with regard to heteropteran venoms. Predaceous species produce venoms that induce rapid paralysis and liquefaction. These venoms are powerfully insecticidal, and may cause paralysis or death when injected into vertebrates. Disulfide-rich peptides, bioactive phospholipids, small molecules such as N,N-dimethylaniline and 1,2,5-trithiepane, and toxic enzymes such as phospholipase A2, have been reported in predatory venoms. However, the detailed composition and molecular targets of predatory venoms are largely unknown. In contrast, recent research into blood-feeding heteropterans has revealed the structure and function of many protein and non-protein components that facilitate acquisition of blood meals. Blood-feeding venoms lack paralytic or liquefying activity but instead are cocktails of pharmacological modulators that disable the host haemostatic systems simultaneously at multiple points. The multiple ways venom is used by heteropterans suggests that further study will reveal heteropteran venom components with a wide range of bioactivities that may be recruited for use as bioinsecticides, human therapeutics, and pharmacological tools.