Guangxitoxin

Add links
Source: Wikipedia, the free encyclopedia.
Guangxitoxin-1E
UniProt
P84835
Search for
StructuresSwiss-model
DomainsInterPro

Guangxitoxin, also known as GxTX, is a peptide toxin found in the

voltage-gated Kv2.1 potassium channel currents, which are prominently expressed in pancreatic β-cells, thus increasing insulin secretion.[1][2]

Sources

Guangxitoxin is found in the venom of the tarantula Plesiophrictus guangxiensis, which lives mainly in Guangxi province of southern China.[2]

Chemistry

Subtypes

Guangxitoxin consists of multiple subtypes, including GxTX-1D, GxTX-1E and GxTX-2.

sequence similarities with Hanatoxin (HaTX), Stromatoxin-1 (ScTx1), and Scodra griseipes toxin (SGTx) peptides.[1][3][4][5] GxTX-1 shows sequence similarities with Jingzhaotoxin-III (JZTX-III), Grammostola spatulata mechanotoxin-4 (GsMTx-4), and Voltage-sensor toxin-1 (VSTX1) peptides.[1][6][7][8] GxTX-1 consists of two variants, GxTX-1D and GxTX-1E, of which GxTX-1E is a more potent inhibitor of Kv2.1.[1]

Sequence

GxTX-1D and GxTX-1E consist of 36 amino acids, differing only a single amino acid at the

glutamate, respectively:[1]

Asp/Glu-Gly-Glu-Cys-Gly-Gly-Phe-Trp-Trp-Lys-Cys-Gly-Ser-Gly-Lys-Pro-Ala-Cys-Cys-Pro-Lys-Tyr-Val-Cys-Ser-Pro-Lys-Trp-Gly-Leu-Cys-Asn-Phe-Pro-Met-Pro

GxTX-2 consists of 33 amino acids, which has only 9 identical amino acids in corresponding sequence compared to GxTX-1D and GxTX-1E:[1] 

Glu-Cys-Arg-Lys-Met-Phe-Gly-Gly-Cys-Ser-Val-Asp-Ser-Asp-Cys-Cys-Ala-His-Leu-Gly-Cys-Lys-Pro-Thr-Leu-Lys-Tyr-Cys-Ala-Trp-Asp-Gly-Thr

Structure

The three-dimensional NMR structure of the toxin reveals an amphipathic part and an inhibitor cystine knot (ICK) motif.[9] The amphipathic part is composed of a large cluster characterized by

lipid membranes effectively with the help of this structure and interact with Kv channels from within the membrane.[10][11][12][13] Differences in distribution of acidic and basic residues compared to SGTx-1 may contribute to the difference in affinity of GxTX-1E for the Kv2.1 channel.[9] Dissimilarities in orientation of loops and turns compared to JZTX-III may contribute to the discrepancy in selectivity of GxTX-1E to the Kv2.1 channel.[9]

Target

GxTX-1E inhibits voltage-gated Kv2.1 channels by modifying its voltage-dependent gating,.

islets.[15] Kv4.3 is mainly of importance in the heart.[16]

The Kv2.1 channel is predominantly expressed in pancreatic β-cells

action potentials.[22] Both the Kv2.2 and Kv4.3 channels are believed not to contribute significantly to the β-cell IDR.[1]

GxTX-1E has no effect on voltage-gated Na+ or Ca2+ channels.[1]

Mode of action

Inhibition of Kv2.1 by GxTX-1E causes a shift in voltage-dependency of activation toward more positive potentials of almost 100 mV.[2] Moreover, GxTX-1E also exhibits properties of decreasing the velocity of hKv2.1 channel opening and increasing the velocity of Kv2.1 channel closing approximately sixfold.[2] By inhibiting Kv2.1 potassium channels, GxTX-1E boosts action potentials of pancreatic β-cells causing mainly increased glucose-stimulated intracellular calcium oscillations which in turn intensifies glucose-stimulated insulin secretion.[1][2] How GxTX-1E is able to generate distinctive calcium oscillations in different cells remains unclear (broader oscillations, increased frequency or restoration of oscillations), however, the specificity of GxTX-1E points in the direction of IDR inhibition causing these effects.

membrane potentials which is only seen in raised glucose levels.[2]

Therapeutic use

Unlike

hypoglycaemia.[1]

References

  1. ^
    PMID 16567526
    .
  2. ^
    PMID 17101164
    .
  3. PMID 7576642
    .
  4. PMID 12065754
    .
  5. PMID 14744131
    .
  6. PMID 15084603
    .
  7. PMID 10779316
    .
  8. S2CID 4396796
    .
  9. ^
    PMID 20509680
    .
  10. S2CID 4329147
    .
  11. S2CID 4426640
    .
  12. PMID 17938232
    .
  13. ^
    PMID 19783984
    .
  14. PMID 21150283
    .
  15. PMID 14988243
    .
  16. PMID 11343410
    .
  17. PMID 12830383
    .
  18. S2CID 4352853
    .
  19. PMID 15950285
    .
  20. PMID 11463864
    .
  21. PMID 8943282
    .
  22. PMID 2197368
    .