Sensory functions like touch and hearing rely on a cell's ability to sense mechanical forces. TRPV channels are a class of evolutionarily conserved mechanosensors. Our research on a metabolic mutant (
pnc-1) with sensory defects has revealed that the nicotinamide (NAM) form of vitamin B3 is a direct agonist for the C. elegans OCR-4/OSM-9 TRPV channel.The enzyme PNC-1 converts NAM to nicotinic acid for NAD+ salvage biosynthesis. In
pnc-1 mutants, NAM levels are increased approximately ten fold and two mechanosensory cell types undergo necrosis. The uterine vulval one (
uv1) cells, which sense stretching of the uterus in the egg laying process, die with high penetrance (>96%). The OLQ neurons, which play a role in foraging and nose touch response, die at a reduced penetrance (28%). Acute treatment of wild-type animals with NAM kills all
uv1 cells within 50 seconds and kills most OLQ cells (79%) within 3 minutes.We noted that a TRPV channel subunit OCR-4 is expressed exclusively in the two cell types that die in the
pnc-1 mutants. So, we investigated the functional relationship between OCR-4 and NAM-induced necrosis. Mutation of
ocr-4 or
osm-9, another TRPV subunit gene, completely rescues NAM-induced
uv1 and OLQ necrosis. Thus, we hypothesized that NAM directly activates the OCR-4/OSM-9 channel and triggers excitatory death by membrane depolarization. We tested this hypothesis by conducting electrophysiology after heterologous expression in Xenopus oocytes. NAM activates the channel formed by co-expression of OCR-4 and OSM-9 with an EC50 of 51.4 uM, a concentration consistent with endogenous NAM levels in
pnc-1 mutants.Furthermore, NAM induces a sensory nose-touch defect in wild-type animals. Nose-touch response is mediated by OCR-2/OSM-9 and TRPA-1 ion channels, not the OCR-4/OSM-9 channel. Hence, NAM may also activate channels formed by other TRPV subunit combinations. The agonist activity of NAM appears to be conserved in Drosophila. Fly homologs of
ocr-4 and
osm-9 are Nanchung and Inactive respectively; they form a heteromeric channel required for hearing. NAM treatment attenuates the response of fly larvae to sound (88% response in untreated vs 14% in NAM-treated larvae). In conclusion, this is the first successful measurement of current derived from heterologously expressed C. elegans TRPV channel. Our research provides a mechanism whereby unanswered questions of TRPV activation and assembly can be studied. Our results also point to intriguing potential metabolic regulation of TRPV channels.