Abstract
BackgroundConotoxins have become a research hotspot in the neuropharmacology field for their high activity and specificity in targeting ion channels and neurotransmitter receptors. There have been reports of a conotoxin acting on two ion channels, but rare reports of a conotoxin acting on three ion channels. MethodsVr3a, a proline-rich M-superfamily conotoxin from a worm-hunting Conus varius, was obtained by solid-phase synthesis and identified by mass spectrometry. The effects of synthesized Vr3a on sodium, potassium and calcium currents were tested on rat DRG cells by patch clamp experiments. The further effects of Vr3a on human Cav1.2 and Cav2.2 currents were tested on HEK293 cells.Results About 10 μM Vr3a has no effects on the peak sodium currents, but can induce a ~10 mV shift in a polarizing direction in the current-voltage relationship. In addition, 10 μM Vr3a can increase 19.61 ± 5.12% of the peak potassium currents and do not induce a shift in the current-voltage relationship. An amount of 10 μM Vr3a can inhibit 31.26% ± 4.53% of the peak calcium currents and do not induce a shift in the current-voltage relationship. The IC50 value of Vr3a on calcium channel currents in rat DRG neurons is 19.28 ± 4.32 μM. Moreover, 10 μM Vr3a can inhibit 15.32% ± 5.41% of the human Cav1.2 currents and 12.86% ± 4.93% of the human Cav2.2 currents.ConclusionsVr3a can simultaneously affect sodium, potassium and calcium currents. This novel triple-target conotoxin Vr3a expands understanding of conotoxin functions.
Highlights
Conotoxins have become a research hotspot in the neuropharmacology field for their high activity and specificity in targeting ion channels and neurotransmitter receptors
There have been reports of a conotoxin acting on two ion channels, but rare reports of a conotoxin acting on three ion channels
Due to the high inhibitory activity of rat tetrodotoxinresistant sodium currents [13], μ-conotoxin SIIIA was used as a preclinical lead for the treatment of pain [14]. μ-conotoxins can be used as sodium channel research probes for their high subtype selectivity, and may be used as neuroprotective agents against hypoxia or oxidative stress [15]
Summary
Conotoxins have become a research hotspot in the neuropharmacology field for their high activity and specificity in targeting ion channels and neurotransmitter receptors. Due to the high specificity and selectivity of conotoxins in targeting ion channels and neurotransmitter receptors, conotoxins have become a research hotspot in the neuropharmacology field [5]. Μ-conotoxins can be used as sodium channel research probes for their high subtype selectivity, and may be used as neuroprotective agents against hypoxia or oxidative stress [15]. In addition to these μ-conotoxins, several other M-superfamily conotoxins were found to inhibit nicotinic acetylcholine receptors or block voltage-gated potassium channels [10,16]. M-1 branch conotoxins have the disulfide connectivity of 1-5, 2-4, 3-6; M-2 branch conotoxins have the disulfide connectivity of 1-6, 2-4, 3-5; while M-4 and M-5 branch conotoxins have the disulfide connectivity of 1-4, 2-5, 3-6 [10]
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