GPR35 modulates Na V 1.9 gating and sensory neuron excitability

Abstract Background and Purpose The voltage‐gated Na + channel Na V 1.9 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 Na V 1.9 function in dorsal root ganglion (DRG) neurons, establishing a previously unrecognized receptor–channel signalling axis. Experimental Approach Transcriptomics of Na V 1.9‐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 Na V 1.9. 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 Na V 1.9‐positive neurons and proximity assays demonstrated spatial association between both proteins in DRG neurons. Activation of GPR35 with cromolyn disodium potentiated Na V 1.9 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 Na V 1.9 currents in a GPR35‐dependent manner, indicating that cGMP‐associated signalling requires GPR35 expression to influence Na V 1.9. Under inflammatory conditions induced by prostaglandin E 2 , GPR35 activation partially attenuated Na V 1.9 potentiation but did not restore normal excitability. Conclusion and Implications These findings identify GPR35 as a regulator of Na V 1.9 and define a receptor–channel signalling module linking GPCR activation to ion channel–dependent modulation of sensory neuron excitability. This work provides a mechanistic framework for understanding GPCR–Na V 1.9 coupling.