A New Sea Anemone Peptide, APETx2, Inhibits ASIC3, a Major Acid-sensitive Channel in Sensory Neurons

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2004 Mar 27

PMID 15044953

Citations 168

Authors

Sylvie Diochot

Anne Baron

Lachlan D Rash

Emmanuel Deval

Pierre Escoubas

Sabine Scarzello

Miguel Salinas

Michel Lazdunski

Affiliations

Soon will be listed here.

Abstract

From a systematic screening of animal venoms, we isolated a new toxin (APETx2) from the sea anemone Anthopleura elegantissima, which inhibits ASIC3 homomeric channels and ASIC3-containing heteromeric channels both in heterologous expression systems and in primary cultures of rat sensory neurons. APETx2 is a 42 amino-acid peptide crosslinked by three disulfide bridges, with a structural organization similar to that of other sea anemone toxins that inhibit voltage-sensitive Na+ and K+ channels. APETx2 reversibly inhibits rat ASIC3 (IC50=63 nM), without any effect on ASIC1a, ASIC1b, and ASIC2a. APETx2 directly inhibits the ASIC3 channel by acting at its external side, and it does not modify the channel unitary conductance. APETx2 also inhibits heteromeric ASIC2b+3 current (IC50=117 nM), while it has less affinity for ASIC1b+3 (IC50=0.9 microM), ASIC1a+3 (IC50=2 microM), and no effect on the ASIC2a+3 current. The ASIC3-like current in primary cultured sensory neurons is partly and reversibly inhibited by APETx2 with an IC50 of 216 nM, probably due to the mixed inhibitions of various co-expressed ASIC3-containing channels.

Citing Articles

Metabolomics study of APETx2 post-conditioning on myocardial ischemia-reperfusion injury.

Li J, Wei Y, Wang Y, Zhang Y, Xu Y, Ma H Front Pharmacol. 2024; 15:1470142.

PMID: 39712499 PMC: 11658994. DOI: 10.3389/fphar.2024.1470142.

Bioactive peptides and proteins for tissue repair: microenvironment modulation, rational delivery, and clinical potential.

Hao Z, Zhang Z, Wang Z, Wang Y, Chen J, Chen T Mil Med Res. 2024; 11(1):75.

PMID: 39639374 PMC: 11619216. DOI: 10.1186/s40779-024-00576-x.

Isolation and cDNA cloning of four peptide toxins from the sea anemone .

Homma T, Ishida M, Nagashima Y, Shiomi K J Venom Anim Toxins Incl Trop Dis. 2024; 30:e20240019.

PMID: 39530114 PMC: 11552618. DOI: 10.1590/1678-9199-JVATITD-2024-0019.

Mechanism of acid-sensing ion channel modulation by Hi1a.

Berger K, MacLean D J Gen Physiol. 2024; 156(12).

PMID: 39446054 PMC: 11513431. DOI: 10.1085/jgp.202313519.

Voltage-clamp fluorometry for advancing mechanistic understanding of ion channel mechanisms with a focus on acid-sensing ion channels.

Centonze E, Kellenberger S Biochem Soc Trans. 2024; 52(5):2167-2177.

PMID: 39400205 PMC: 11555705. DOI: 10.1042/BST20240165.

References

Mamet J, Lazdunski M, Voilley N . How nerve growth factor drives physiological and inflammatory expressions of acid-sensing ion channel 3 in sensory neurons. J Biol Chem. 2003; 278(49):48907-13. DOI: 10.1074/jbc.M309468200. View

Lingueglia E, Champigny G, Lazdunski M, Barbry P . Cloning of the amiloride-sensitive FMRFamide peptide-gated sodium channel. Nature. 1995; 378(6558):730-3. DOI: 10.1038/378730a0. View

Waldmann R, Champigny G, Voilley N, Lauritzen I, Lazdunski M . The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans. J Biol Chem. 1996; 271(18):10433-6. DOI: 10.1074/jbc.271.18.10433. View

England L, Imperial J, Jacobsen R, Craig A, Gulyas J, Akhtar M . Inactivation of a serotonin-gated ion channel by a polypeptide toxin from marine snails. Science. 1998; 281(5376):575-8. DOI: 10.1126/science.281.5376.575. View

Mamet J, Baron A, Lazdunski M, Voilley N . Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci. 2002; 22(24):10662-70. PMC: 6758460. View

Poet M, Tauc M, Lingueglia E, Cance P, Poujeol P, Lazdunski M . Exploration of the pore structure of a peptide-gated Na+ channel. EMBO J. 2001; 20(20):5595-602. PMC: 125683. DOI: 10.1093/emboj/20.20.5595. View

De Weille J, Bassilana F, Lazdunski M, Waldmann R . Identification, functional expression and chromosomal localisation of a sustained human proton-gated cation channel. FEBS Lett. 1998; 433(3):257-60. DOI: 10.1016/s0014-5793(98)00916-8. View

Benson C, Eckert S, McCleskey E . Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. Circ Res. 1999; 84(8):921-8. DOI: 10.1161/01.res.84.8.921. View

Deval E, Baron A, Lingueglia E, Mazarguil H, Zajac J, Lazdunski M . Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. Neuropharmacology. 2003; 44(5):662-71. DOI: 10.1016/s0028-3908(03)00047-9. View

10.

Bode F, Sachs F, Franz M . Tarantula peptide inhibits atrial fibrillation. Nature. 2001; 409(6816):35-6. DOI: 10.1038/35051165. View

11.

Tytgat J, Chandy K, Garcia M, Gutman G, Martin-Eauclaire M, Van der Walt J . A unified nomenclature for short-chain peptides isolated from scorpion venoms: alpha-KTx molecular subfamilies. Trends Pharmacol Sci. 1999; 20(11):444-7. DOI: 10.1016/s0165-6147(99)01398-x. View

12.

Escoubas P, Bernard C, Lambeau G, Lazdunski M, Darbon H . Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels. Protein Sci. 2003; 12(7):1332-43. PMC: 2323924. DOI: 10.1110/ps.0307003. View

13.

Khera P, Blumenthal K . Role of the cationic residues arginine 14 and lysine 48 in the function of the cardiotonic polypeptide anthopleurin B. J Biol Chem. 1994; 269(2):921-5. View

14.

Diochot S, Loret E, Bruhn T, Beress L, Lazdunski M . APETx1, a new toxin from the sea anemone Anthopleura elegantissima, blocks voltage-gated human ether-a-go-go-related gene potassium channels. Mol Pharmacol. 2003; 64(1):59-69. DOI: 10.1124/mol.64.1.59. View

15.

Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M . A proton-gated cation channel involved in acid-sensing. Nature. 1997; 386(6621):173-7. DOI: 10.1038/386173a0. View

16.

Sluka K, Price M, Breese N, Stucky C, Wemmie J, Welsh M . Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain. 2003; 106(3):229-239. DOI: 10.1016/S0304-3959(03)00269-0. View

17.

Driscoll P, Gronenborn A, Beress L, Clore G . Determination of the three-dimensional solution structure of the antihypertensive and antiviral protein BDS-I from the sea anemone Anemonia sulcata: a study using nuclear magnetic resonance and hybrid distance geometry-dynamical simulated annealing. Biochemistry. 1989; 28(5):2188-98. DOI: 10.1021/bi00431a033. View

18.

Norton R . Structure and structure-function relationships of sea anemone proteins that interact with the sodium channel. Toxicon. 1991; 29(9):1051-84. DOI: 10.1016/0041-0101(91)90205-6. View

19.

Pan H, Longhurst J, Eisenach J, Chen S . Role of protons in activation of cardiac sympathetic C-fibre afferents during ischaemia in cats. J Physiol. 1999; 518 ( Pt 3):857-66. PMC: 2269450. DOI: 10.1111/j.1469-7793.1999.0857p.x. View

20.

Chen C, England S, Akopian A, Wood J . A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A. 1998; 95(17):10240-5. PMC: 21492. DOI: 10.1073/pnas.95.17.10240. View