Targeting Supramolecular Active Complexes of Nav1.7/Nav1.8 to Relieve Chronic Neuropathic Pain
Abstract
Neuropathic pain (NP) affects 7%-10% of population, with current treatments often proving inadequate. Here we show that Nav1.7 and Nav1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Nav1.7/Nav1.8 SMACs. Targeting these SMACs with combined Nav1.7 and Nav1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na+ potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.
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