TRPV 3 Regulates NOS-Independent Nitric Oxide Synthesis in the Skin

Nitric oxide (NO) is an unstable signaling molecule synthesized de novo mainly from L-arginine by NO synthase enzymes (NOS). Nitrite reduction can also produce NO, predominantly within body fluids (e.g. saliva, sweat, and blood plasma) and under extreme hypoxic and acidic conditions. It remains unknown if intracellular canonical signaling pathways regulate nitritedependent NO production. We examined NO production in the skin, a hypoxic tissue enriched in nitrites where NO plays important roles in wound-healing and other biological processes. Here we show that activation of TRPV3, a heat-activated transient receptor potential (TRP) ion channel expressed in keratinocytes, induces NO production via a nitrite-dependent pathway. TRPV3 and nitrite are involved in keratinocyte migration in vitro and in wound-healing and thermosensory behaviors in vivo. Our study demonstrates that activation of an ion channel can induce NOSindependent NO production in keratinocytes.