posted on 2021-06-07, 12:04authored byYan Jiang, Joel Castro, Linda V. Blomster, Akello J. Agwa, Jessica Maddern, Gudrun Schober, Volker Herzig, Chun Yuen Chow, Fernanda C. Cardoso, Paula Demétrio De Souza França, Junior Gonzales, Christina I. Schroeder, Steffen Esche, Thomas Reiner, Stuart M. Brierley, Glenn F. King
The human nociceptor-specific voltage-gated
sodium channel 1.7
(hNaV1.7) is critical for sensing various types of somatic
pain, but it appears not to play a primary role in acute visceral
pain. However, its role in chronic visceral pain remains to be determined.
We used assay-guided fractionation to isolate a novel hNaV1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide
that potently inhibits hNaV1.7 (IC50 = 10 nM),
with greater than 100-fold selectivity over hNaV1.3–hNaV1.6, 45-fold selectivity over hNaV1.1, and 24-fold
selectivity over hNaV1.2. Tsp1a is a gating modifier that
inhibits NaV1.7 by inducing a hyperpolarizing shift in
the voltage-dependence of channel inactivation and slowing recovery
from fast inactivation. NMR studies revealed that Tsp1a adopts a classical
knottin fold, and like many knottin peptides, it is exceptionally
stable in human serum. Remarkably, intracolonic administration of
Tsp1a completely reversed chronic visceral hypersensitivity in a mouse
model of irritable bowel syndrome. The ability of Tsp1a to reduce
visceral hypersensitivity in a model of irritable bowel syndrome suggests
that pharmacological inhibition of hNaV1.7 at peripheral
sensory nerve endings might be a viable approach for eliciting analgesia
in patients suffering from chronic visceral pain.