A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain

Bohlen, Christopher J.; Priel, Avi; Zhou, Shi-Sheng; King, David S.; Siemens, Jan; Julius, David

doi:10.1016/j.cell.2010.03.052

Cited by 289 publications

(426 citation statements)

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“…Indeed, we have successfully exploited this approach to probe structure-function relationships of sensory TRP channels. For example, the analysis of avian-mammalian or amphibian-mammalian TRPV1 chimeras led to the identification of amino acids that specify sensitivity to capsaicin or peptide toxins, respectively (33,34). A similar approach revealed sites within the cold receptor, TRPM8 (35), that determine sensitivity to cooling compounds (36).…”

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confidence: 99%

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cordero-Morales¹,

Gracheva²,

Julius

2011

Proc. Natl. Acad. Sci. U.S.A.

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196

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Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide array of physical and chemical stimuli, making them important components of sensory systems in both vertebrate and invertebrate organisms. Mammalian TRPA1 channels are activated by chemically reactive irritants, whereas snake and Drosophila TRPA1 orthologs are preferentially activated by heat. By comparing human and rattlesnake TRPA1 channels, we have identified two portable heat-sensitive modules within the ankyrin repeat-rich aminoterminal cytoplasmic domain of the snake ortholog. Chimeric channel studies further demonstrate that sensitivity to chemical stimuli and modulation by intracellular calcium also localize to the N-terminal ankyrin repeat-rich domain, identifying this region as an integrator of diverse physiological signals that regulate sensory neuron excitability. These findings provide a framework for understanding how restricted changes in TRPA1 sequence account for evolution of physiologically diverse channels, also identifying portable modules that specify thermosensitivity.chemosensation | pain | thermosensation | calcium modulation | somatosensation P rimary afferent (somatosensory) neurons detect a range of physical and chemical stimuli, including temperature, pressure, and noxious irritants (1). The transient receptor potential (TRP) channel family has been shown to play a predominant role in these processes, particularly in regard to thermosensitivity and chemosensitivity (2-5). TRPA1, otherwise known as the "wasabi receptor," plays a key role in somatosensation in evolutionarily diverse phyla, including vertebrate and invertebrate species. Mammalian TRPA1 is expressed by primary afferent sensory neurons of the pain pathway, where it functions as a sensor of environmental and endogenous chemical irritants, such as allyl isothiocyanate (AITC), acrolein, and 4-hydroxynonena, and contributes to cellular mechanisms underlying inflammatory pain (6-9).TRPA1 channels show species-specific functional variation to suit their physiological roles. For example, snakes are unique among vertebrates in that their TRPA1 channels are heat-sensitive, which some species (rattlesnakes, boas, and pythons) have exploited to detect infrared radiation (10). Similarly, insect TRPA1 channels are heat-sensitive and contribute to thermal avoidance behaviors (11)(12)(13)(14). In these cases, however, thermosensitivity comes at the expense of chemosensitivity, such that AITC and other chemical irritants still activate these channels but with reduced potency compared with mammalian orthologs (10). Despite clear physiological differences between snake and mammalian TRPA1 channels, they share significant amino acid identity (56%), providing a unique opportunity to exploit sequence comparisons and domain swaps to pinpoint structural elements associated with stimulus detection and/or gating. Delineating elements that contribute to TRPA1 function will provide insights into the evolutionary process whereby structural changes lead t...

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confidence: 99%

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cordero-Morales¹,

Gracheva²,

Julius

2011

Proc. Natl. Acad. Sci. U.S.A.

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196

188

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“…This signature may be reduced to the more general principal structural motif CX 6 CX n CC (C 1 X 6 C 2 X 5 C 4 C 5 in our case), and extra structural motif CXCX n CXC (C 6 XC 7 X m C 8 XC 9 in our case) that are characteristic of spider neurotoxins [23]. The principal structural motif and the extra structural motif in turn conform to the more general ICK motif CX 2-7 CX 3-11 CX 0-7 CX 1-17 CX [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] …”

Section: Ottx Sequence Analysismentioning

confidence: 91%

“…The first identified examples of modular spider toxins were cyto-insectotoxins in the venom of L. tarabaevi, which contain two linear modules (AMP+AMP) [18]. Subsequently, two-domain spider toxins containing two knottin modules (ICK+ICK) were discovered in the venom of Cheiracanthium punctorium (Miturgidae) and Haplopelma schmidti (Theraphosidae) [16,19]. Thus, modular toxins are quite widespread in spiders, and further studies will probably reveal even greater diversity.…”

Section: Diversity Of Modular Toxins In Spidersmentioning

confidence: 99%

“…To date, we have described the following combinations: (a) ICK+ICK, two ICK domains in one toxin [16], (b) ICK+AMP, an ICK domain with a long linear C-terminal extension conferring membrane activity [17], and (c) AMP+AMP, two short linear MAPs joined into one long structure [18]. Other research groups have also described modular toxins of the ICK+ICK [19] and ICK+AMP types [20].…”

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confidence: 99%

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Spider toxins comprising disulfide‐rich and linear amphipathic domains: a new class of molecules identified in the lynx spider Oxyopes takobius

et al. 2013

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In addition to the conventional neurotoxins and cytotoxins, venom of the lynx spider Oxyopes takobius was found to contain two-domain modular toxins named spiderines: OtTx1a, 1b, 2a and 2b. These toxins show both insecticidal activity (a median lethal dose against flesh fly larvae of 75 lgÁg À1) and potent antimicrobial effects (minimal inhibitory concentrations in the range 0.1-10 lM). Full sequences of the purified spiderines were established by a combination of Edman degradation, mass spectrometry and cDNA cloning. They are relatively large molecules (~110 residues, 12.0-12.5 kDa) and consist of two distinct modules separated by a short linker. The N-terminal part (~40 residues) contains no cysteine residues, is highly cationic, forms amphipathic a-helical structures in a membrane-mimicking environment, and shows potent cytolytic effects on cells of various origins. The C-terminal part (~60 residues) is disulfide-rich (five S-S bonds), and contains the inhibitor cystine knot (ICK/knottin) signature. The N-terminal part of spiderines is very similar to linear cytotoxic peptides found in various organisms, whereas the C-terminal part corresponds to the usual spider neurotoxins. We synthesized the modules of OtTx1a and compared their activity to that of full-length mature toxin produced recombinantly, highlighting the importance of the N-terminal part, which retained full-length toxin activity in both insecticidal and antimicrobial assays. The unique structure of spiderines completes the range of two-domain spider toxins. DatabaseThe protein sequences of the spiderines (OtTx) reported in this paper have been submitted to the UniProt Knowledgebase (UniProtKB) under accession numbers P86716-P86719, and the nucleotide sequences encoding OtTx have been submitted to the GenBank under accession numbers JX134894-JX134897.

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“…anandamide, arachidonic acid metabolites such as N-arachidonoyl-dopamine [NADA], 12-hydroperoxyeicosatetraenoic acid, oxidized linoleic acid metabolites, essential oils, octadecadienoids), and a variety of pungent plant products as exemplified by capsaicin (responsible for the piquancy of hot chilli peppers), resiniferatoxin, piperine (the pungent ingredient in black pepper), gingerol and zingerone (from ginger), camphor, as well as eugenol (a powerful essential oil found in cloves). Interestingly (and somewhat unexpectedly), TRPV1 is also activated by ethanol and venoms from jellyfish and spiders [9,[40][41][42][43][44][45][46][47][48][49].…”

Section: Trpv1 As Polymodal Sensor Expressed On Peptidergic Sensory Nmentioning

confidence: 94%

TRPV1 Antagonists as Analgesic Agents

Trevisani

Gatti²

2013

TOPAINJ

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Abstract:The last decade (2001 -2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This review focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seemingly unrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this important side effect.

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A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain

Cited by 289 publications

References 54 publications

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli

Spider toxins comprising disulfide‐rich and linear amphipathic domains: a new class of molecules identified in the lynx spider Oxyopes takobius

TRPV1 Antagonists as Analgesic Agents

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