AsKC11, a Kunitz Peptide from <i>Anemonia sulcata</i>, Is a Novel Activator of G Protein-Coupled Inward-Rectifier Potassium Channels
2022
Dongchen An | Ernesto Lopes Pinheiro-Junior | László Béress | Irina Gladkikh | Elena Leychenko | Eivind A. B. Undheim | Steve Peigneur | Jan Tytgat
(1) Background: G protein-coupled inward-rectifier potassium (GIRK) channels, especially neuronal GIRK1/2 channels, have been the focus of intense research interest for developing drugs against brain diseases. In this context, venom peptides that selectively activate GIRK channels can be seen as a new source for drug development. Here, we report on the identification and electrophysiological characterization of a novel activator of GIRK1/2 channels, AsKC11, found in the venom of the sea anemone <i>Anemonia sulcata</i>. (2) Methods: AsKC11 was purified from the sea anemone venom by reverse-phase chromatography and the sequence was identified by mass spectrometry. Using the two-electrode voltage-clamp technique, the activity of AsKC11 on GIRK1/2 channels was studied and its selectivity for other potassium channels was investigated. (3) Results: AsKC11, a Kunitz peptide found in the venom of <i>A. sulcata</i>, is the first peptide shown to directly activate neuronal GIRK1/2 channels independent from Gi/o protein activity, without affecting the inward-rectifier potassium channel (IRK1) and with only a minor effect on K<sub>V</sub>1.6 channels. Thus, AsKC11 is a novel activator of GIRK channels resulting in larger K<sup>+</sup> currents because of an increased chord conductance. (4) Conclusions: These discoveries provide new insights into a novel class of GIRK activators.
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