Introduction
Guangxitoxin 1E is a KV2.1 and KV2.2 specific channel blocker (IC50 values are 1-3 nM). The experimental results showed that it enhances glucose-stimulated insulin secretion from human islets in vitro, but not from islet cells lacking the KV2.1 channel. Besides, it has no significant effect on plasma insulin, glucagon or blood glucose levels in mice, but increases plasma somatostatin levels.
Pharmacologic action
Although the mechanism that guangxitoxin 1E can produce [Ca2+]i is not clear entirely, the specificity of guangxitoxin 1E indicates that the effects are due to blocking the delayed rectifier current. Besides, guangxitoxin 1E has no effect on resting membrane potential or [Ca2+]i in low glucose. The potential explanation for this phenomenon is that guangxitoxin 1E has restricted access to the core of the islet where b-cells predominantly reside. KV2.1 channels likely make a major contribution to the delayed rectifier current in both mouse and rat β-cells, based on guangxitoxin 1E sensitivity.
Function
Similar effects to plasma gelsolin (pGSN), guangxitoxin 1E inhibited gp120 enhancement of IK and associated neuronal apoptosis. Guangxitoxin 1E has been studied extensively on mouse β-cells. Besides, guangxitoxin 1E inhibits nearly 90% of the mouse β-cell delayed rectifier current at +20mV and prolongs action potentials triggered by glucose. Glucose-stimulated oscillations in [Ca2+]i are enhanced by Guangxitoxin 1E. It has been observed that there were several types of [Ca2+]i responses to guangxitoxin 1E. Experiment shows [Ca2+]i oscillations become broader in guangxitoxin 1E in some cells, while the frequency increases in others. Furthermore, guangxitoxin 1E restores oscillations that have waned. As expected for an inhibitor of delayed rectifier channels, guangxitoxin 1E has no effect on insulin secretion in low glucose.
Pharmacokinetics and metabolism
Guangxitoxin 1E enhances glucose-dependent insulin secretion from mouse islets. The EC50 is about 400 nM in intact islets, roughly 100-fold higher than the IC50 for h KV2.1 inhibition. Besides, guangxitoxin 1E potently stimulates insulin secretion from dispersed islet cells. As the result of the experiment showed, Guangxitoxin 1E shifts the voltage-dependence of gating of delayed rectifier channels in the mouse β-cell. Moreover, in rat β-cells in the presence of guangxitoxin 1E, a transient outward current is seen in most cells.
References:
Herrington, J. (2007). Gating modifier peptides as probes of pancreatic β-cell physiology. Toxicon, 49(2), 231-238.
Liu, H., Liu, J., Liang, S., & Xiong, H. (2013). Plasma gelsolin protects HIV-1 gp120-induced neuronal injury via voltage-gated K+ channel Kv2. 1. Molecular and Cellular Neuroscience, 57, 73-82.
Herrington, J., Zhou, Y. P., Bugianesi, R. M., Dulski, P. M., Feng, Y., Warren, V. A., ... & Wagner, M. (2006). Blockers of the delayed-rectifier potassium current in pancreatic β-cells enhance glucose-dependent insulin secretion. Diabetes, 55(4), 1034-1042.
