The function of the transient receptor potential vanilloid type 1
capsaicin receptor is subject to modulation by phosphorylation catalyzed by various
enzymes including
protein kinase C and
cAMP-dependent protein kinase. The aim of this study was to compare the significance of the basal and stimulated activity of
protein kinase C and
cAMP-dependent protein kinase in transient receptor potential vanilloid type 1 receptor responsiveness in the rat in vitro by measurement of the intracellular
calcium concentration in cultured trigeminal ganglion neurons and in vivo by determination of the behavioral noxious heat threshold.
KT5720, a selective inhibitor of
cAMP-dependent protein kinase, reduced the
calcium transients induced by
capsaicin or the other, much more potent transient receptor potential vanilloid type 1 receptor agonist
resiniferatoxin in trigeminal sensory neurons and diminished the drop of the noxious heat threshold (heat
allodynia) evoked by intraplantar
resiniferatoxin injection.
Chelerythrine chloride, a selective inhibitor of
protein kinase C, failed to alter either of these responses, although it inhibited the effect of
phorbol 12-myristate 13-acetate in the in vitro assay.
Staurosporine, a rather nonselective
protein kinase inhibitor, failed to reduce the
capsaicin- and
resiniferatoxin-induced
calcium transients but inhibited the
resiniferatoxin-evoked heat
allodynia. Dibutyryl-cAMP and
phorbol 12-myristate 13-acetate, activator(s) of
cAMP-dependent protein kinase and
protein kinase C, respectively, enhanced the effect of
capsaicin in the
calcium uptake assay while
forskolin, an activator of
adenylyl cyclase, augmented that of
resiniferatoxin in the heat
allodynia model. None of the
protein kinase inhibitors or activators altered the
calcium transients evoked by high
potassium, a nonspecific depolarizing stimulus. It is concluded that basal activity of
cAMP-dependent protein kinase, unlike
protein kinase C, is involved in the maintenance of transient receptor potential vanilloid type 1 receptor function in somata of trigeminal sensory neurons but stimulation of either
cAMP-dependent protein kinase or
protein kinase C above the resting level can lead to an enhanced transient receptor potential vanilloid type 1 receptor responsiveness. Similar mechanisms are likely to operate in vivo in peripheral terminals of nociceptive dorsal root ganglion neurons.