Abstract
Spider venoms contain a vast array of bioactive peptides targeting ion channels. A large number of peptides have high potency and selectivity toward sodium channels. Nav1.7 contributes to action potential generation and propagation and participates in pain signaling pathway. In this study, we describe the identification of μ-TRTX-Ca2a (Ca2a), a novel 35-residue peptide from the venom of Vietnam spider Cyriopagopus albostriatus (C. albostriatus) that potently inhibits Nav1.7 (IC50 = 98.1 ± 3.3 nM) with high selectivity against skeletal muscle isoform Nav1.4 (IC50 > 10 μM) and cardiac muscle isoform Nav1.5 (IC50 > 10 μM). Ca2a did not significantly alter the voltage-dependent activation or fast inactivation of Nav1.7, but it hyperpolarized the slow inactivation. Site-directed mutagenesis analysis indicated that Ca2a bound with Nav1.7 at the extracellular S3–S4 linker of domain II. Meanwhile, Ca2a dose-dependently attenuated pain behaviors in rodent models of formalin-induced paw licking, hot plate test, and acetic acid-induced writhing. This study indicates that Ca2a is a potential lead molecule for drug development of novel analgesics.
Highlights
Voltage-gated sodium channels (VGSCs) are important integral membrane proteins expressed in electrically excitable cells
We described the identification and characterization of a novel peptide μ-TRTX-Ca2a, which is a 35-residue peptide toxin isolated from the venom of tarantula spider C. albostriatus with six cysteines and belongs to the ICK motif
Ca2a inhibited Nav1.2, Nav1.3, Nav1.6, and Nav1.7 channels but had negligible effect on Nav1.4, Nav1.5, Nav1.8, and Nav1.9 channels, suggesting that Ca2a is a selective antagonist of neuronal TTX-S VGSCs
Summary
Voltage-gated sodium channels (VGSCs) are important integral membrane proteins expressed in electrically excitable cells. The opening of pore-forming α subunits causes an influx of sodium ions, which is essential for action potential generation and propagation. The α subunits are organized in four homologous domains (DI–DIV), each of which consists of six transmembrane α helices (S1–S6) connected by extracellular and intracellular loops. Nine distinct VGSC α subunits (Nav1.1–1.9) and four β subunits have been cloned from mammals (Dib-Hajj et al, 2010). Compelling genetic studies and clinical evidence have revealed the importance of human Nav1.7 (hNav1.7) as an analgesic target (Dib-Hajj et al, 2009; Wang et al, 2011; Gingras et al, 2014)
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