Abstract
Analysis of small dorsal root ganglion (DRG) neurons revealed novel functions for vanilloid receptor 1 (VR1) in the regulation of cytosolic Ca(2+). The VR1 agonist capsaicin induced Ca(2+) mobilization from intracellular stores in the absence of extracellular Ca(2+), and this release was inhibited by the VR1 antagonist capsazepine but was unaffected by the phospholipase C inhibitor xestospongins, indicating that Ca(2+) mobilization was dependent on capsaicin receptor binding and was not due to intracellular inositol-1,4,5-trisphosphate generation. Confocal microscopy revealed extensive expression of VR1 on endoplasmic reticulum, consistent with VR1 operating as a Ca(2+) release receptor. The main part of the capsaicin-releasable Ca(2+) store was insensitive to thapsigargin, a selective endoplasmic reticulum Ca(2+)-ATPase inhibitor, suggesting that VR1 might be predominantly localized to a thapsigargin-insensitive endoplasmic reticulum Ca(2+) store. In addition, VR1 was observed to behave as a store-operated Ca(2+) influx channel. In DRG neurons, capsazepine attenuated Ca(2+) influx following thapsigargin-induced Ca(2+) store depletion and inhibited thapsigargin-induced inward currents. Conversely, transfected HEK-293 cells expressing VR1 showed enhanced Ca(2+) influx and inward currents following Ca(2+) store depletion. Combined data support topographical and functional diversity for VR1 in the regulation of cytosolic Ca(2+) with the plasma membrane-associated form behaving as a store-operated Ca(2+) influx channel and endoplasmic reticulum-associated VR1 possibly functioning as a Ca(2+) release receptor in sensory neurons.
Highlights
Analysis of small dorsal root ganglion (DRG) neurons revealed novel functions for vanilloid receptor 1 (VR1) in the regulation of cytosolic Ca2؉
The VR1 antagonist capsazepine (10 M) induced a slow release of Ca2ϩ from intracellular stores and abrogated the capsaicin-induced transient increase in [Ca2ϩ]i (Fig. 2c), suggesting that capsaicin-induced Ca2ϩ release was dependent on capsaicin receptor binding and that capsazepine probably acts as a partial agonist for this receptor-mediated Ca2ϩ release
Combined data from this study are supportive of a multifaceted role for VR1 in regulating [Ca2ϩ]i in small sized DRG neurons with topographical cellular location possibly dictating whether this receptor functions as a facilitator of Ca2ϩ release from intracellular stores or Ca2ϩ influx across the plasma membrane
Summary
Analysis of small dorsal root ganglion (DRG) neurons revealed novel functions for vanilloid receptor 1 (VR1) in the regulation of cytosolic Ca2؉. The effect of CPZ on store depletion-activated inward currents induced by Tg was assessed in capsaicin-sensitive small sized DRG neurons in the presence of extracellular Ca2ϩ
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