GPR35 modulates NaV1.9 gating and sensory neuron excitability
Abstract
Background and purpose: The voltage-gated Na+ channel NaV1.9 is a determinant of excitability in sensory neurons, yet the upstream G-protein-coupled receptors (GPCRs) that regulate its activity remain poorly defined. Here, we identify GPR35 as a modulator of NaV1.9 function in dorsal root ganglion (DRG) neurons, establishing a previously unrecognized receptor-channel signalling axis.
Experimental approach: Transcriptomics of NaV1.9-expressing neurons, proximity ligation assays, patch-clamp electrophysiology in primary mouse DRG neurons and a genetic mouse model were combined to assess spatial and functional relationships between GPR35 and NaV1.9. Pharmacological activation of GPR35 was examined using cromolyn disodium, whereas zaprinast and sildenafil were used to probe potential cGMP-dependent mechanisms.
Key results: GPR35 transcripts were enriched in NaV1.9-positive neurons and proximity assays demonstrated spatial association between both proteins in DRG neurons. Activation of GPR35 with cromolyn disodium potentiated NaV1.9 currents, accelerated channel gating and modified neuronal excitability, reflected by increased action potential overshoot and upstroke velocity. These effects were absent from GPR35-deficient DRG neurons. Zaprinast and the phosphodiesterase-5 inhibitor sildenafil also potentiated NaV1.9 currents in a GPR35-dependent manner, indicating that cGMP-associated signalling requires GPR35 expression to influence NaV1.9. Under inflammatory conditions induced…
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