Abstract
Multiple representatives of eulipotyphlan mammals such as shrews have oral venom systems. Venom facilitates shrews to hunt and/or hoard preys. However, little is known about their venom composition, and especially the mechanism to hoard prey in comatose states for meeting their extremely high metabolic rates. A toxin (BQTX) was identified from venomous submaxillary glands of the shrew Blarinella quadraticauda. BQTX is specifically distributed and highly concentrated (~ 1% total protein) in the organs. BQTX shares structural and functional similarities to toxins from snakes, wasps and snails, suggesting an evolutional relevancy of venoms from mammalians and non-mammalians. By potentiating thrombin and factor-XIIa and inhibiting plasmin, BQTX induces acute hypertension, blood coagulation and hypokinesia. It also shows strong analgesic function by inhibiting elastase. Notably, the toxin keeps high plasma stability with a 16-h half-life in-vivo, which likely extends intoxication to paralyze or immobilize prey hoarded fresh for later consumption and maximize foraging profit.
Similar content being viewed by others
Data availability
Data are available on request from the corresponding author.
Code availability
Not applicable.
References
Fox RC, Scott CS (2006) First evidence of a venom delivery apparatus in extinct mammals. Nature 435(7045):1091–1093. https://doi.org/10.1038/nature03646
Rode-Margono J, Nekaris K (2015) Cabinet of curiosities: venom systems and their ecological function in mammals, with a focus on primates. Toxins 7(7):2639–2658. https://doi.org/10.3390/toxins7072639
Ligabue-Braun R, Verli H (2012) Venomous mammals: a review. Toxicon 59(7):680–695. https://doi.org/10.1016/j.toxicon.2012.02.012
Dufton MJ (1992) Venomous mammals. Pharmacol Therapeut 53(2):199–215. https://doi.org/10.1016/0163-7258(92)90009-O
Bowen CV, Debay D (2013) In Vivo detection of human TRPV6-rich tumors with anti-cancer peptides derived from soricidin. PLoS ONE 8(3):e58866. https://doi.org/10.1371/journal.pone.0058866
Whittington CM, Papenfuss AT (2010) Novel venom gene discovery in the platypus. Genome Biol 11(9):R95. https://doi.org/10.1186/gb-2010-11-9-r95
Torres AM, Bansal P (2014) Structure and antimicrobial activity of platypus ‘intermediate’ defensin-like peptide. FEBS Lett 588(9):1821–1826. https://doi.org/10.1016/j.febslet.2014.03.044
Grow NB, Nekaris KAI (2015) Does toxic defence in Nycticebus spp. relate to ectoparasites? The lethal effects of slow loris venom on arthropods. Toxicon 95(1):1–5. https://doi.org/10.1016/j.toxicon.2014.12.005
Nekaris KAI, Moore RS (2013) Mad, bad and dangerous to know: the biochemistry, ecology and evolution of slow loris venom. J Venom Anim Toxins 19(1):21. https://doi.org/10.1186/1678-9199-19-21
Ma D, Mizurini DM (2013) Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo. Blood 122(25):4094–4106. https://doi.org/10.1182/blood-2013-08-517474
Low D, Sunagar K (2013) Dracula’s children: molecular evolution of vampire bat venom. J Proteomics 89(26):95–111. https://doi.org/10.1016/j.jprot.2013.05.034
Folins KE, Müller J (2007) Canine grooves: morphology, function, and relevance to venom. J Vertebr Paleontol 27(2):547–551. https://doi.org/10.1671/0272-4634(2007)27[547:CGMFAR]2.0.CO;2
Ariano-Sánchez D (2008) Envenomation by a wild Guatemalan Beaded LizardHeloderma horridum charlesbogerti. Clin Toxicol 46(9):897–899. https://doi.org/10.1080/15563650701733031
Kaila F, Kaila E (2013) Evolution of venom across extant and extinct eulipotyphlans L’évolution du venin chez les eulipotyphles modernes et éteints. CR Palevol 12(7):531–542. https://doi.org/10.1016/j.crpv.2013.05.004
Nicholas RC, Daniel P (2019) Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals. Proc Natl Acad Sci USA 116(15):25745–25755. https://doi.org/10.1073/pnas.1906117116
Kita M, Nakamura Y (2004) Blarina toxin, a mammalian lethal venom from the short-tailed shrew Blarina brevicauda: Isolation and characterization. Proc Natl Acad Sci USA 101(20):7542–7547. https://doi.org/10.1073/pnas.0402517101
Kowalski K, Rychlik L (2008) The role of venom in the hunting and hoarding of prey differing in body size by the Eurasian water shrew, Neomys fodiens. J Mammal 99(2):351–362. https://doi.org/10.1093/jmammal/gyy013
Kita M, Okumura Y (2005) Purification and characterisation of blarinasin, a new tissue kallikrein-like protease from the short-tailed shrew Blarina brevicauda: comparative studies with blarina toxin. Biol Chem. https://doi.org/10.1515/bc.2005.022
Churchfield S (1990) The natural history of shrews. Q Rev Biol 66(4):505–506. https://doi.org/10.1086/417393
Taylor JRE (1998) Evolution of energetic strategies in shrews. In: Jan MW (ed) Evolution of shrews, 1st edn. Bialowieza, Mammal Research Institute, pp 309–346
Hamilton WJ (1930) The food of the soricidae. J Mammal 11(1):26–39. https://doi.org/10.2307/1373782
Hotopp KP (2002) Land snails and soil calcium in central appalachian mountain forest. Southeastern Nat 1(1):27–44. https://doi.org/10.1656/1528-7092(2002)001[0027:lsasci]2.0.co;2
Dehnel A (1960) Aufspeicherung von Nahrungsvorräten durch Sorex araneus Linnaeus 1758; Gromadzenie zapasów pożywienia u Sorex araneus Linnaeus 1758. Acta Theriol 4:265–268. https://doi.org/10.4098/AT.arch.60-14
Martin IG (1984) Factors affecting food hoarding in the short-tailed shrew Blarina brevicauda. Mammalia 48(1):65–72. https://doi.org/10.1515/mamm.1984.48.1.65
Rychlik L (2002) Prey size, prey nutrition, and food handling by shrews of different body sizes. Behav Ecol 13(2):216–223. https://doi.org/10.1093/beheco/13.2.216
Jiang XL, Wang YX (2003) A review of the systematics and distribution of Asiatic short-tailed shrews, genus Blarinella (Mammalia: Soricidae). Mamm Biol 68(4):193–204. https://doi.org/10.1078/1616-5047-00085
He K, Li YJ (2010) A multi-locus phylogeny of Nectogalini shrews and influences of the paleoclimate on speciation and evolution. Mol Phylogenet Evol 56(2):734–746. https://doi.org/10.1016/j.ympev.2010.03.039
Martin IG (1982) Venom of the short-tailed shrew (Blarina brevicauda) as an insect immobilizing agent. J Mammal 5(1):189–192. https://doi.org/10.2307/1380494
Arinos M, Richardson M (2007) Purification and properties of a coagulant thrombin-like enzyme from the venom of Bothrops leucurus. Comp Biochem Physiol A Mol Integr Physiol 146(4):565–575. https://doi.org/10.1016/j.cbpa.2005.12.033
Zhang Z, Lan G (2014) A potent anti-thrombosis peptide (vasotab TY) from horsefly salivary glands. Int J Biochem Cell Biol 54(8):83–88. https://doi.org/10.1016/j.biocel.2014.07.004
Yue M, Luo D (2015) Misshapen/NIK-related Kinase (MINK1) is involved in platelet function, hemostasis and thrombus formation. Blood 127(7):927–937. https://doi.org/10.1182/blood-2015-07-659185
Xia Q, Wang X (2012) Inhibition of platelet aggregation by curdione from Curcuma wenyujin essential Oil. Thromb Res 130(3):409–414. https://doi.org/10.1016/j.thromres.2012.04.005
Yang S, Xiao Y (2013) Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models. Proc Natl Acad Sci USA 110(43):17534–17539. https://doi.org/10.1073/pnas.1306285110
Fernández J, Gutiérrez J (2016) Characterization of a novel snake venom component: Kazal-type inhibitor-like protein from the arboreal pitviper Bothriechis schlegelii. Biochimie 125:83–90. https://doi.org/10.1016/j.biochi.2016.03.004
Watkins M, Hillyard DR (2006) Genes expressed in a turrid venom duct: divergence and similarity to conotoxins. J Mol Evol 62(3):247–256. https://doi.org/10.1007/s00239-005-0010-x
Yan Z, Fang Q (2016) Insights into the venom composition and evolution of an endoparasitoid wasp by combining proteomic and transcriptomic analyses. Sci Rep 6(1):19604. https://doi.org/10.1038/srep19604
Ablondi FB, Hagan JJ (1959) Inhibition of plasmin, trypsin and the streptokinase-activated fibrinolytic system by 6-aminocaproic acid. Arch Biochem Biophys 82(1):153–160. https://doi.org/10.1016/0003-9861(59)90100-6
Vicuña L, Strochlic DE (2015) The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell–derived leukocyte elastase. Nat Med 21(5):518–523. https://doi.org/10.1038/nm.3852
Bode W (1992) Natural protein proteinase inhibitors and their interaction with proteinases. Eur J Biochem 204(2):433–451. https://doi.org/10.1111/j.1432-1033.1992.tb16654.x
Waisberg M, Mizurini DM (2014) Plasmodium falciparum infection induces expression of a mosquito salivary protein (Agaphelin) that targets neutrophil function and inhibits thrombosis without impairing hemostasis. PLoS Pathog 10(9):e1004338. https://doi.org/10.1371/journal.ppat.1004338
Aaron M, LeBeau PS (2009) Prostate-specific antigen is a “chymotrypsin-like” serine protease with unique P1 substrate specificity. Biochemistry 48(15):3490–3496. https://doi.org/10.1021/bi9001858
Zheng LS, Cao Y (2016) SPINK6 promotes metastasis of nasopharyngeal carcinoma via binding and activation of epithelial growth factor receptor. Cancer Res 77(2):579–589
Pierre LS, Earl ST (2008) Common evolution of waprin and kunitz-like toxin families in Australian venomous snakes. Cell Mol Life Sci 65(24):4039–4054. https://doi.org/10.1007/s00018-008-8573-5
Viala VL, Hildebrand D (2005) Venomics of the Australian eastern brown snake (Pseudonaja textilis): detection of new venom proteins and splicing variants. Toxicon 107:252–265. https://doi.org/10.1016/j.toxicon.2015.06.005
Cheng AC (1840) Tsai IH (2014) Functional characterization of a slow and tight-binding inhibitor of plasmin isolated from Russell's viper venom. Biochim Biophys Acta Gen Subj 1:153–159. https://doi.org/10.1016/j.bbagen.2013.08.019
Wan H, Lee KS (2013) A spider-derived Kunitz-type serine protease inhibitor that acts as a plasmin inhibitor and an elastase inhibitor. PLoS One 8(1): https://doi.org/10.1371/journal.pone.0053343
Choo YM, Lee KS (2012) Antifibrinolytic Role of a Bee Venom Serine Protease Inhibitor That Acts as a Plasmin Inhibitor. PLoS ONE. 7(2): https://doi.org/10.1371/journal.pone.0032269
Söllner C, Mentele R, Eckerskorn C, Fritz H, Sommerhoff CP (2010) Isolation and characterization of hirustasin, an antistasin-type serine-proteinase inhibitor from the medical leech Hirudo medicinalis. Eur J Biochem 219(3):937–943. https://doi.org/10.1111/j.1432-1033.1994.tb18575.x
Myles T, Church FC (1998) Role of thrombin anion-binding exosite-I in the formation of thrombin-serpin complexes. J Biol Chem 273(47):31203–31208. https://doi.org/10.1074/jbc.273.47.31203
Tang X, Zhang Z (2020) Transferrin plays a central role in coagulation balance by interacting with clotting factors. Cell Res 30(2):119–132. https://doi.org/10.1101/646075
Tang X, Fang M (2020) Iron-deficiency and estrogen are associated with ischemic stroke by up-regulating transferrin to induce hypercoagulability. Cir Res 127(5):651–663. https://doi.org/10.1161/CIRCRESAHA.119.316453
Lagos F, Elgheznawy A (2021) Secreted modular calcium binding protein 1 binds/activates thrombin to account for platelet hyper-reactivity in diabetes. Blood 137(12):1641–1651. https://doi.org/10.1182/blood.2020009405
Robert EW (2008) The short-tailed shrew and field mouse predation. J Mammal 25(4):359–364. https://doi.org/10.2307/1374897
Buchalczyk T, Pucek Z (1963) Food storage of the European water shrew, Neomys fodiens (Pennant, 1771); Gromadzenie pokarmu przez rzsorka, Neomys fodiens (Pennant, 1771). Acta Theriol 7:376–379. https://doi.org/10.4098/AT.arch.63-22
Tomasi TE (1978) Function of venom in the short-tailed shrew Blarina brevicauda. J Mammal 59(4):852–854. https://doi.org/10.2307/1380150
Acknowledgements
We acknowledge English language support from Dr. Peter Muiruri Kamau and all the participants of this study.
Funding
This work was supported by the National Science Foundation of China (31930015, 32100907, 81770464, and 32070443), Chinese Academy of Sciences (XDB31000000 and KFJ-STS-SCYD-304), Chongqing Municipal Education Commission (HZ2021020), and Yunnan Province (2019FA006, 2019FB127, 2019ZF003, and 202003AD150008), as well as the Ministry of Science and Technology of China (2018YFA0801403).
Author information
Authors and Affiliations
Contributions
ZL, XT, WC, XJ, ZD, LL, and XH performed research; XJ, ZC, KH, and QL Collected Blarinella quadraticauda specimens and analyzed toxicological effects; W.C. provided B. quadraticauda bite case report; RL, XT, ZL, MR, and PK wrote the paper.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
All animal-based experiments conformed to the recommendations in the Guide for the Care and Use of Laboratory Animals of the Kunming Institute of Zoology, Chinese Academy of Sciences. All experiments complied with national legislation and were approved by the Committee on the Ethics of Animal Experiments of the Kunming Institute of Zoology, Chinese Academy of Sciences (SYXK-2014-0007 and SMKX-2016013).
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Consent for publication
The authors affirm that human research participants provided informed consent for publication of the image in Fig. S1C.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Liao, Z., Tang, X., Chen, W. et al. Shrew's venom quickly causes circulation disorder, analgesia and hypokinesia. Cell. Mol. Life Sci. 79, 35 (2022). https://doi.org/10.1007/s00018-021-04116-x
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00018-021-04116-x