Changes in osmolality modulate voltage-gated sodium channels in trigeminal ganglion neurons

Voltage-gated sodium channels (VGSCs) are important channels which participate in many physiological functions. Whether VGSCs can be modulated by changes in osmolality in trigeminal ganglion (TG) neurons remains unknown. In this study, by using whole-cell patch clamp techniques, we tested the effects of hypo- and hypertonicity on VGSCs in cultured TG neurons. Our data show that tetrodotoxin-resistant sodium current (TTX-R current) was inhibited in the presence of hypo- and hypertonic solutions. In hypertonic solutions both voltage-dependent activation and inactivation curves shifted to the hyperpolarizing direction, while in hypotonic solutions only inactivation curve shifted to the hyperpolarizing direction. Transient Receptor Potential Vanilloid 4 (TRPV4) receptor activator mimicked the inhibition of TTX-R current by hypotonicity and the inhibition by hypotonicity was markedly attenuated by TRPV4 receptor blocker and in TRPV4(-/-) mice TG neurons. We also demonstrate that the inhibition of PKA selectively attenuated hypotonicity-induced inhibition, whereas antagonism of PLC and PI3K selectively attenuated hypertonicity-induced inhibition. We conclude that although hypo- and hypertonicity have similar effect on VGSCs, receptor and intracellular signaling pathways are different for hypo- versus hypertonicity-induced inhibition of TTX-R current.