Abstract
Intermediate-conductance Ca2+-activated K+ (IK) channels are calcium/calmodulin-regulated voltage-independent K+ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to be potent activators of IK channels. However, the poor selectivity of these molecules limits their therapeutic value. Venom-derived peptides usually block their targets with high specificity. Therefore, we searched for novel peptide activators of IK channels by testing a series of toxins from spiders. Using electrophysiological experiments, we identified hainantoxin-I (HNTX-I) as an IK-channel activator. HNTX-I has little effect on voltage-gated Na+ and Ca2+ channels from rat dorsal root ganglion neurons and on the heterologous expression of voltage-gated rapidly activating delayed rectifier K+ channels (human ether-à-go-go-related gene; human ERG) in HEK293T cells. Only 35.2% ± 0.4% of the currents were activated in SK channels, and there was no effect on BK channels. We demonstrated that HNTX-I was not a phrenic nerve conduction blocker or acutely toxic. This is believed to be the first report of a peptide activator effect on IK channels. Our study suggests that the activity and selectivity of HNTX-I on IK channels make HNTX-I a promising template for designing new drugs for cardiovascular diseases.
Highlights
The intermediate-conductance Ca2+-activated K+ (IK) channels belong to the gene family of calcium/calmodulin-regulated and voltage-independent K+ channels (SK1/SK2/SK3 and IK) [1] and contribute to cellular functions by producing membrane hyperpolarization, regulating intracellular
Many studies in animals and even clinical studies have shown that decreased IK-channel activity is associated with endothelial dysfunction in cardiovascular diseases
Endothelium-dependent vasodilatation is mediated by nitric oxide (NO), prostacyclin and an endothelium-derived hyperpolarizing factor (EDHF), and it involves IK channels [5]
Summary
The intermediate-conductance Ca2+-activated K+ (IK) channels belong to the gene family of calcium/calmodulin-regulated and voltage-independent K+ channels (SK1/SK2/SK3 and IK) [1] and contribute to cellular functions by producing membrane hyperpolarization, regulating intracellular. IK channel modulators mainly comprise small organic compounds and venom-derived peptides [6] These different classes of chemicals modulate the channel by binding to either the external or the internal face of the ion-conducting pore. In keeping with the uncertain or weak selectivity of some of the activators, caution is indicated in interpreting results when using higher dosages in vitro and in vivo [8] For this reason, we screened for peptide-positive gating modulators from venom-derived peptides as alternatives to the existing small organic activators. Our previous works demonstrated that HNTX-I shows no effect on the neuronal TTX-S VGSCs in adult rat dorsal root ganglion neurons nor does it target VGSCs in cardiac or skeletal muscles of mammals It selectively blocks rNav1.2/β1 and para/tipE channels expressed in Xenopus laevis oocytes. A phrenic nerve conduction study and a toxicity test of mouse increase the pharmaceutical value of HNTX-I
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