Lack of interaction between prostaglandin E 2 receptor subtypes in regulating adenylyl cyclase activity in cultured rat dorsal root ganglion cells

Abstract

The hyperalgesic response to prostaglandin E 2 (PGE 2) is thought to be mediated by activation of the cAMP/protein kinase A pathway in primary sensory neurones. The aim of this study was to investigate the relative contribution of different PGE 2 (EP) receptor subtypes to the overall activity of adenylyl cyclase in adult rat isolated dorsal root ganglion (DRG) cells, in vitro. PGE 2 and the prostanoid EP 4 receptor agonist ONO-AE1-329 increased [ 3H]cAMP production with EC 50 values of 500 nM and 70 nM, respectively, and showed similar efficacies. No combination of prostanoid EP 1, EP 2, EP 3 or EP 4 receptor selective agonists produced synergistic increases in [ 3H]cAMP. The prostacyclin mimetic cicaprost increased [ 3H]cAMP production with an EC 50 value of 42 nM and produced a significantly greater maximal response compared with PGE 2. No evidence for prostanoid EP 3 receptor-dependent inhibition of adenylyl cyclase activity could be obtained to account for the relatively weak effect of PGE 2 compared with prostacyclin receptor agonists. Interestingly, sulprostone (prostanoid EP 3/EP 1 receptor agonist) caused a Rho-kinase-dependent retraction of neurites, suggesting an alternative role for prostanoid EP 3 receptors in DRG cells. In conclusion, PGE 2 mediated increases in adenylyl cyclase activity in primary sensory neurones is likely to be mediated by activation of prostanoid EP 4 receptors, and is not under inhibitory control by prostanoid EP 3 receptors.