Calcium entry via TRPV1 but not ASICs induces neuropeptide release from sensory neurons.

Inflammatory mediators induce neuropeptide release from nociceptive nerve endings and cell bodies, causing increased local blood flow and vascular leakage resulting in edema. Neuropeptide release from sensory neurons depends on an increase in intracellular Ca(2+) concentration. In this study we investigated the role of two types of pH sensors in acid-induced Ca(2+) entry and neuropeptide release from dorsal root ganglion (DRG) neurons. The transient receptor potential vanilloid 1 channel (TRPV1) and acid-sensing ion channels (ASICs) are both H(+)-activated ion channels present in these neurons, and are therefore potential pH sensors for this process. We demonstrate with in situ hybridization and immunocytochemistry that TRPV1 and several ASIC subunits are co-expressed with neuropeptides in DRG neurons. The activation of ASICs and of TRPV1 led to an increase in intracellular Ca(2+) concentration. While TRPV1 has a high Ca(2+) permeability and allows direct Ca(2+) entry when activated, we show here that ASICs of DRG neurons mediate Ca(2+) entry mostly by depolarization-induced activation of voltage-gated Ca(2+) channels and only to a small extent via the pore of Ca(2+)-permeable ASICs. Extracellular acidification led to the release of the neuropeptide calcitonin gene-related peptide from DRG neurons. The pH dependence and the pharmacological profile indicated that TRPV1, but not ASICs, induced neuropeptide secretion. In conclusion, this study shows that although both TRPV1 and ASICs mediate Ca(2+) influx, TRPV1 is the principal sensor for acid-induced neuropeptide secretion from sensory neurons.