Psalmotoxin Explained

Psalmotoxin
Symbol:PcTx1
Pdb:1lmm
Uniprot:P60514
Organism:Psalmopoeus cambridgei
Footnotes:See TCDB 8.B.10

Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula Psalmopoeus cambridgei.[1] [2] It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel.

Sources

Psalmotoxin is a toxin produced in the venom glands of the South American tarantula Psalmopoeus cambridgei.[2]

Chemistry

The psalmotoxin structure can be classified as an inhibitor cystine knot (ICK) protein. Many ion channel effectors from snail, spider, and scorpion venoms share a similar ICK structure, although they possess very different pharmalogical profiles. Among ICK toxins, psalmotoxin is the only peptide known to act on homomeric ASIC1 channels.[3]

Psalmotoxin is a 40-amino acid peptide, possessing 6 cysteines linked by three disulfide bridges. The three-dimensional structure consists of a compact disulfide-bonded core from which three loops and the N and C termini emerge. The main element of the structure is a three-stranded antiparallel β-sheet.[4]

Target

Psalmotoxin can bind to a particular isoform of the Acid Sensing Ion Channel, the Acid Sensing Ion Channel 1 (ASIC1).[5] The binding of psalmotoxin has an effect on both of the two splice variants known of ASIC1, ASIC1a and ASIC1b.[6] ASIC1 has two transmembrane components. After the first transmembrane component it forms a large extracellular bridge with the second transmembrane component, an extracellular loop. This extracellular loop contains cysteine rich domains. Psalmotoxin specifically binds these cysteine rich domains in the extracellular loop of ASIC1. This implicates this domain is the receptor site of ASIC1 for psalmotoxin.[7]

ASICs are proton-gated sodium channels. ASICs open when H+ binds. This occurs when the H+-concentration in the environment of the neuron is slightly higher compared to resting H+-concentrations (pH = 7.4).[6]

The expression of ASIC1a is high in both the central nervous system and in the sensory neurons of the dorsal root ganglia. ASIC1b is only expressed in sensory neurons. Expression of ASIC1a in the central nervous system relates to the involvement of ASIC1a in higher brain functions, such as learning, memory and fear conditioning.[8] Expression of ASIC1a and ASIC1b in sensory neurons relates to their involvement in nociception[9] [10] [11] [12] and taste.[13]

Mode of action

Binding of psalmotoxin to ASIC1a is reported to increase the affinity of ASIC1a for H+. This increase in affinity for H+ results in the shift of ASIC1a into the desensitized state at resting H+-concentrations (pH = 7.4). The channel being desensitized means that the ion channel is bound to its ligand, H+, but is not able to let ions pass through the ion channel. The underlying mechanism of how this increase in affinity for H+ accounts for a shift of the ASIC1a channels into the desensitized state is not yet specified.[6]

Psalmotoxin also interacts with ASIC1b. In contrast to psalmotoxin binding to ASIC1a, binding of psalmotoxin to ASIC1b results in promoting the opening of the channel. This agonistic effect of psalmotoxin on ASIC1b only occurs in slightly acidic conditions (pH = 7.1).[14]

Toxicity

The role of psalmotoxin in prey capture and the importance of ASIC1a channels as targets of venom components remains unclear.[1]

Therapeutic uses

Psalmotoxin is currently not used for therapeutic purposes, but understanding the psalmotoxin/ASIC1a interaction may be of therapeutic value. Recently, it has been shown that activation of ASIC1a during the acidosis accompanying brain ischemia leads to significant Ca2+ influx, which contributes to neuronal cell death. Inhibition of ASIC1a by psalmotoxin significantly decreased ischemic neuronal cell death. Therefore, it is suggested that desensitized ASIC1's by pharmacological intervention could be beneficial for patients at risk of having a stroke.[15] For the same reasons, psalmotoxin could contribute in the search for a cure for gliomas.[16] Inhibition of ASIC1a in the amygdala by psalmotoxin could have an anxiolytic effect.[17] As ASIC's play a role in nociception, psalmotoxin could be helpful in designing new analgesic drugs acting directly against pain at the nociceptor level.[2]

See also

Notes and References

  1. Book: Abba J. . Kastin . Handbook of biologically active peptides . Academic Press . 2006 . 369–380 (376) . 978-0-12-369442-3 . Graham M. . Nicholson . Spider Venom Peptides . https://books.google.com/books?id=n8SV9iM6kT0C&pg=PA369 . 71846806.
  2. Mazzuca M, Heurteaux C, Alloui A, Diochot S, Baron A, Voilley N, Blondeau N, Escoubas P, Gélot A, Cupo A, Zimmer A, Zimmer AM, Eschalier A, Lazdunski M . A tarantula peptide against pain via ASIC1a channels and opioid mechanisms . Nature Neuroscience . 10 . 8 . 943–5 . August 2007 . 17632507 . 10.1038/nn1940 . 19381729 .
  3. 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 Science . 12 . 7 . 1332–43 . July 2003 . 12824480 . 2323924 . 10.1110/ps.0307003 .
  4. Escoubas P, De Weille JR, Lecoq A, Diochot S, Waldmann R, Champigny G, Moinier D, Ménez A, Lazdunski M . Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels . The Journal of Biological Chemistry . 275 . 33 . 25116–21 . August 2000 . 10829030 . 10.1074/jbc.M003643200 . free .
  5. Qadri YJ, Berdiev BK, Song Y, Lippton HL, Fuller CM, Benos DJ . Psalmotoxin-1 docking to human acid-sensing ion channel-1 . The Journal of Biological Chemistry . 284 . 26 . 17625–33 . June 2009 . 19395383 . 2719401 . 10.1074/jbc.M109.003913 . free .
  6. Chen X, Kalbacher H, Gründer S . The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity . The Journal of General Physiology . 126 . 1 . 71–9 . July 2005 . 15955877 . 2266618 . 10.1085/jgp.200509303 .
  7. Salinas M, Rash LD, Baron A, Lambeau G, Escoubas P, Lazdunski M . The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a . The Journal of Physiology . 570 . Pt 2 . 339–54 . January 2006 . 16284080 . 1464308 . 10.1113/jphysiol.2005.095810 .
  8. Wemmie JA, Chen J, Askwith CC, Hruska-Hageman AM, Price MP, Nolan BC, Yoder PG, Lamani E, Hoshi T, Freeman JH, Welsh MJ . The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory . Neuron . 34 . 3 . 463–77 . April 2002 . 11988176 . 10.1016/S0896-6273(02)00661-X . free .
  9. Sutherland SP, Benson CJ, Adelman JP, McCleskey EW . Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons . Proceedings of the National Academy of Sciences of the United States of America . 98 . 2 . 711–6 . January 2001 . 11120882 . 14653 . 10.1073/pnas.011404498 . free .
  10. Voilley N, de Weille J, Mamet J, Lazdunski M . Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors . The Journal of Neuroscience . 21 . 20 . 8026–33 . October 2001 . 10.1523/JNEUROSCI.21-20-08026.2001 . 11588175 . 6763876 .
  11. Mamet J, Baron A, Lazdunski M, Voilley N . Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels . The Journal of Neuroscience . 22 . 24 . 10662–70 . December 2002 . 10.1523/JNEUROSCI.22-24-10662.2002 . 12486159 . 6758460 .
  12. Chen CC, Zimmer A, Sun WH, Hall J, Brownstein MJ, Zimmer A . A role for ASIC3 in the modulation of high-intensity pain stimuli . Proceedings of the National Academy of Sciences of the United States of America . 99 . 13 . 8992–7 . June 2002 . 12060708 . 124411 . 10.1073/pnas.122245999 . 2002PNAS...99.8992C . free .
  13. Ugawa S, Yamamoto T, Ueda T, Ishida Y, Inagaki A, Nishigaki M, Shimada S . Amiloride-insensitive currents of the acid-sensing ion channel-2a (ASIC2a)/ASIC2b heteromeric sour-taste receptor channel . The Journal of Neuroscience . 23 . 9 . 3616–22 . May 2003 . 10.1523/JNEUROSCI.23-09-03616.2003 . 12736332 . 6742202 .
  14. Chen X, Kalbacher H, Gründer S . Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent . The Journal of General Physiology . 127 . 3 . 267–76 . March 2006 . 16505147 . 2151504 . 10.1085/jgp.200509409 .
  15. Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, MacDonald JF, Wemmie JA, Price MP, Welsh MJ, Simon RP . Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels . Cell . 118 . 6 . 687–98 . September 2004 . 15369669 . 10.1016/j.cell.2004.08.026 . free .
  16. Ross SB, Fuller CM, Bubien JK, Benos DJ . Amiloride-sensitive Na+ channels contribute to regulatory volume increases in human glioma cells . American Journal of Physiology. Cell Physiology . 293 . 3 . C1181-5 . September 2007 . 17615161 . 10.1152/ajpcell.00066.2007 .
  17. Dwyer JM, Rizzo SJ, Neal SJ, Lin Q, Jow F, Arias RL, Rosenzweig-Lipson S, Dunlop J, Beyer CE . Acid sensing ion channel (ASIC) inhibitors exhibit anxiolytic-like activity in preclinical pharmacological models . Psychopharmacology . 203 . 1 . 41–52 . March 2009 . 18949460 . 10.1007/s00213-008-1373-7 . 19373513 .

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