Two tarantula peptides inhibit activation of multiple sodium channels

Biochemistry. 2002 Dec 17;41(50):14734-47. doi: 10.1021/bi026546a.


Two peptides, ProTx-I and ProTx-II, from the venom of the tarantula Thrixopelma pruriens, have been isolated and characterized. These peptides were purified on the basis of their ability to reversibly inhibit the tetrodotoxin-resistant Na channel, Na(V) 1.8, and are shown to belong to the inhibitory cystine knot (ICK) family of peptide toxins interacting with voltage-gated ion channels. The family has several hallmarks: cystine bridge connectivity, mechanism of channel inhibition, and promiscuity across channels within and across channel families. The cystine bridge connectivity of ProTx-II is very similar to that of other members of this family, i.e., C(2) to C(16), C(9) to C(21), and C(15) to C(25). These peptides are the first high-affinity ligands for tetrodotoxin-resistant peripheral nerve Na(V) channels, but also inhibit other Na(V) channels (IC(50)'s < 100 nM). ProTx-I and ProTx-II shift the voltage dependence of activation of Na(V) 1.5 to more positive voltages, similar to other gating-modifier ICK family members. ProTx-I also shifts the voltage dependence of activation of Ca(V) 3.1 (alpha(1G), T-type, IC(50) = 50 nM) without affecting the voltage dependence of inactivation. To enable further structural and functional studies, synthetic ProTx-II was made; it adopts the same structure and has the same functional properties as the native peptide. Synthetic ProTx-I was also made and exhibits the same potency as the native peptide. Synthetic ProTx-I, but not ProTx-II, also inhibits K(V) 2.1 channels with 10-fold less potency than its potency on Na(V) channels. These peptides represent novel tools for exploring the gating mechanisms of several Na(V) and Ca(V) channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / isolation & purification
  • Calcium Channel Blockers / pharmacology
  • Cell Line
  • Disulfides / chemistry
  • Electrophysiology
  • Humans
  • Ion Channel Gating / drug effects
  • Molecular Sequence Data
  • Peptides / chemistry
  • Peptides / isolation & purification
  • Peptides / pharmacology*
  • Potassium Channel Blockers / chemistry
  • Potassium Channel Blockers / isolation & purification
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Rats, Wistar
  • Sodium Channel Blockers / chemistry
  • Sodium Channel Blockers / isolation & purification
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / metabolism*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Spider Venoms / chemistry
  • Spider Venoms / isolation & purification
  • Spider Venoms / pharmacology*


  • Calcium Channel Blockers
  • Disulfides
  • Peptides
  • Potassium Channel Blockers
  • ProTx-I peptide
  • ProTx-II peptide
  • Sodium Channel Blockers
  • Sodium Channels
  • Spider Venoms

Associated data

  • SWISSPROT/P83476
  • SWISSPROT/P83480