A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1

Yang, Shilong; Yang, Fan; Wang, Ningning; Hong, Jing; Li, Bowen; Luo, Lei; Rong, Mingqiang; Yarov‐Yarovoy, Vladimir; Zheng, Jie; Wang, Kewei; Lai, Ren

doi:10.1038/ncomms9297

Cited by 104 publications

(167 citation statements)

References 58 publications

(100 reference statements)

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“…Noticeably, recent studies using centipede and spider toxins 6,21 , Mg 2+ 49,50 , and Na + 51 provided fresh evidence that, together with existing findings (summarized in ref. 52), suggests that the outer pore region is involved in the heat activation process.…”

Section: Discussionmentioning

confidence: 58%

“…The situation motivated the search in recent years for chemical stimuli that activate TRPV1 through the heat activation pathway. Candidates identified so far include divalent cations such as Mg 2+ and Ba 2+ 49,50 , Na + 51 , DkTx 21 and RhTx 6 . While drastically different in size, all of these modulators are found to be effective only when applied from the extracellular side, with their likely binding sites clustered at the outer pore region.…”

Section: Discussionmentioning

confidence: 99%

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Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

Yang

et al. 2017

Biophysical Journal

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TRPV1 is a polymodal nociceptor for diverse physical and chemical stimuli that interact with different parts of the channel protein. Recent cryo-EM studies revealed detailed channel structures, opening the door for mapping structural elements mediating activation by each stimulus. Towards this goal, here we have combined unstructured peptide-insertion screening (UPS) with electrophysiological and fluorescence recordings to explore structural and functional roles of the intracellular regions of TRPV1 in mediating various activation stimuli. We found that most of the tightly packed protein regions did not tolerate structural perturbation by UPS when tested, indicating that structural integrity of the intracellular region is critical. In agreement with previous reports, Ca 2+ -dependent desensitization is strongly dependent on both intracellular N-and C-terminal domains; insertions of an unstructured peptide between these domains and the transmembrane core domain nearly eliminated Ca 2+ -dependent desensitization. In contrast, channel activations by capsaicin, low pH, divalent cations, and even heat are mostly intact in mutant channels containing the same insertions. These observations suggest that the transmembrane core domain of TRPV1, but not the intracellular domains, is responsible for sensing these stimuli.TRPV1 ion channel can be directly activated or modulated by capsaicin 1 , heat 1 , extracellular proton 2 , divalent cations 3 , Na + 4 , peptide toxins from spider 5 , centipede 6 , and scorpion 7 , membrane depolarization 8 , intracellular Ca 2+ 9 , and many other factors 10 . A noticeable feature of TRPV1 polymodal activation emerging from biophysical investigations is the existence of non-overlapping activation pathways [11][12][13] . However, except for capsaicin 14-19 , proton 11,20 , and animal toxins 6,21 , the channel structures that sense activation stimuli are poorly defined. Recent cryo-EM studies revealed that the transmembrane core domain of TRPV1 resembles that of tetrameric cation channels, with six transmembrane helical segments surrounding a centrally located ion permeation pore 22,23 . The partially resolved intracellular N-and C-terminal domains contain special structures such as the ankyrin-like repeat domains and the TRP domain that likely play crucial structural and/or functional roles 10 . Arrangement of intracellular domains has been investigated using fluorescence resonance energy transfer 24 . A major task for TRPV1 study in the post-structure era is to assign functional roles to individual structure domains.The unstructured peptide-insertion screening (UPS) strategy had been used to rapidly and reliably obtain information on structure-function relationships in an ion channel even before detailed protein structures were available. In one effective application, isolating the pore domain of yeast TRPY1 channel from the intracellular Ca 2+ -sensing domain with unstructured peptides demonstrated that the pore domain was mechanosensitive 25 . Similarly, unstructured peptide insertion...

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

Yang

et al. 2017

Biophysical Journal

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“…The first reported structure of a centipede venom peptide was that of µ-SLPTX 3 -Ssm6a (henceforth just Ssm6a), a three-disulfide, 46-residue peptide from the Chinese red-headed centipede Scolopendra subspinipes mutilans (Figure 3a,b) [35]. The all-helical 3D structure of Ssm6a revealed that it is derived from a family of ubiquitous ecdysozoan peptide hormones known as the ion transport peptide/crustacean hyperglycemic hormone (ITP/CHH) family [35].…”

Section: The Slptx3 Fold: Weaponization Of a Hormonementioning

confidence: 99%

“…Rho-toxin (RhTx) is a 27-residue peptide ( Figure 4a) isolated from the venom of S. subspinipes mutilans [46]. It contains four cysteines with a pattern typical of the SLPTX4 family.…”

Section: The Slptx4 Fold: Rho-toxinmentioning

confidence: 99%

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Centipede venoms as a source of drug leads

Undheim

Jenner

King

2016

Expert Opinion on Drug Discovery

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Introduction: Centipedes are one of the oldest and most successful lineages of venomous terrestrial predators. Despite their use for centuries in traditional medicine, centipede venoms remain poorly studied. However, recent work indicates that centipede venoms are highly complex chemical arsenals that are rich in disulfide-constrained peptides that have novel pharmacology and three-dimensional structure. Areas covered:This review summarizes what is currently know about centipede venom proteins, with a focus on disulfide-rich peptides that have novel or unexpected pharmacology that might be useful from a therapeutic perspective. We also highlight the remarkable diversity of constrained threedimensional peptide scaffolds present in these venoms that might be useful for bioengineering of drug leads. Expert opinion:The resurgence of interest in peptide drugs has stimulated interest in venoms as a source of highly stable, disulfide-constrained peptides with potential as therapeutics. Well-studied venomous taxa such as cone snails and snakes have yielded FDA-approved drugs, while ancient invertebrate predators such as spiders and sea anemones have yielded molecules that are currently in preclinical studies and clinical trials, respectively. However, until recently, the paucity of research on centipede venoms made it easy to discount them as a potential source of peptides with therapeutically useful properties. Seminal studies over the past five years have revealed that centipede venoms have exceedingly complex proteomes that are perhaps richer than any other venom in unique disulfide-rich peptide scaffolds. Like most arthropod predators, centipede venoms are rich in peptides that target neuronal ion channels and receptors, but it is also becoming increasingly apparent that many of these peptides have novel or unexpected pharmacological properties with potential applications in drug discovery and development.

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Rational Design of a Modality‐Specific Inhibitor of TRPM8 Channel against Oxaliplatin‐Induced Cold Allodynia

et al. 2021

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Platinum-based compounds in chemotherapy such as oxaliplatin often induce peripheral neuropathy and neuropathic pain such as cold allodynia in patients. Transient Receptor Potential Melastatin 8 (TRPM8) ion channel is a nociceptor critically involved in such pathological processes. Direct blockade of TRPM8 exhibits significant analgesic effects but also incurs severe side effects such as hypothermia. To selectively target TRPM8 channels against cold allodynia, a cyclic peptide DeC-1.2 is de novo designed with the optimized hot-spot centric approach. DeC-1.2 modality specifically inhibited the ligand activation of TRPM8 but not the cold activation as measured in single-channel patch clamp recordings. It is further demonstrated that DeC-1.2 abolishes cold allodynia in oxaliplatin treated mice without altering body temperature, indicating DeC-1.2 has the potential for further development as a novel analgesic against oxaliplatin-induced neuropathic pain.

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A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1

Cited by 104 publications

References 58 publications

Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

Exploring Functional Roles of TRPV1 Intracellular Domains with Unstructured Peptide-Insertion Screening

Centipede venoms as a source of drug leads

Rational Design of a Modality‐Specific Inhibitor of TRPM8 Channel against Oxaliplatin‐Induced Cold Allodynia

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