Guangxitoxin
Guangxitoxin, also known as GxTX, is a peptide toxin found in the venom of the tarantula "Plesiophrictus guangxiensis". It primarily inhibits outward voltage-gated K2.1 potassium channel currents, which are prominently expressed in pancreatic β-cells, thus increasing insulin secretion. Sources. Guangxitoxin is found in the venom of the tarantula "Plesiophrictus guangxiensis", which lives mainly in Guangxi province of southern China. Chemistry. Subtypes. Guangxitoxin consists of multiple subtypes, including GxTX-1D, GxTX-1E and GxTX-2. GxTX-2 shows sequence similarities with Hanatoxin (HaTX), Stromatoxin-1 (ScTx1), and "Scodra griseipes" toxin (SGTx) peptides. GxTX-1 shows sequence similarities with Jingzhaotoxin-III (JZTX-III), "Grammostola spatulata  mechanotoxin-4 (GsMTx-4), and Voltage-sensor toxin-1 (VSTX1) peptides. GxTX-1 consists of two variants, GxTX-1D and GxTX-1E, of which GxTX-1E is a more potent inhibitor of K2.1. Sequence. GxTX-1D and GxTX-1E consist of 36 amino acids, differing only a single amino acid at the NH-terminal, aspartate or glutamate, respectively: 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 	Guangxitoxin
666092	corresponding sequence compared to GxTX-1D and GxTX-1E: 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. The amphipathic part is composed of a large cluster characterized by solvent-exposed hydrophobic residues which is enclosed by acidic and basic residues. The ICK motif contains three disulfide bonds stabilizing the toxin structure. The conserved amphipathic structure assists in 	Guangxitoxin
666093	binding the toxin and can be explained since similar toxins allocate into lipid membranes effectively with the help of this structure and interact with K channels from within the membrane. Differences in distribution of acidic and basic residues compared to SGTx-1 may contribute to the difference in affinity of GxTX-1E for the K2.1 channel. Dissimilarities in orientation of loops and turns compared to JZTX-III may contribute to the discrepancy in selectivity of GxTX-1E to the K2.1 channel. Target. GxTX-1E inhibits voltage-gated K2.1 channels by modifying its voltage-dependent gating. mutations in the S3b-S4 paddle motif of the 	Guangxitoxin
666094	voltage-sensing domain of K2.1 reduce affinity for tarantula toxins. Two other voltage-gated potassium channels inhibited by GxTX-1 are the K2.2 and K4.3 channels. K2.2 is located predominantly in δ-cells of primate islets. K4.3 is mainly of importance in the heart. The K2.1 channel is predominantly expressed in pancreatic β-cells and in the central nervous system. In pancreatic β-cells, K2.1 comprises 60% of the currents mediated by K channels. Furthermore, the K2.1 channel shows similar biophysical properties to the delayed rectifier K current (I) of the β-cells. This makes GxTX appropriate to study the physiological 	Guangxitoxin
666095	role of the aforementioned current as it inhibits 90% of the β-cell I. The I is thought to play an important role in repolarization of action potentials. Both the K2.2 and K4.3 channels are believed not to contribute significantly to the β-cell I. GxTX-1E has no effect on voltage-gated Na or Ca channels. Mode of action. Inhibition of K2.1 by GxTX-1E causes a shift in voltage-dependency of activation toward more positive potentials of almost 100 mV. Moreover, GxTX-1E also exhibits properties of decreasing the velocity of hK2.1 channel opening and increasing the velocity of K2.1 channel 	Guangxitoxin
666096	closing approximately sixfold. By inhibiting K2.1 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. 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 I inhibition causing these effects. Notably, GxTX-1E stimulated insulin secretion is specifically glucose dependent, considering that I is only active above -20mV membrane potentials which is only seen in raised glucose levels. Therapeutic use. Unlike K 	Guangxitoxin
666097	channel blockers, GxTX-1 primarily blocks I and demonstrates a potential target for future drugs in diabetes mellitus type 2 treatment, since a blockade of I should not provoke hypoglycaemia.