The cAMP transduction cascade mediates the PGE2-induced inhibition of potassium currents in rat sensory neurones

The role of the cyclic AMP (cAMP) transduction cascade in mediating the prostaglandin E 2 (PGE 2 )-induced decrease in potassium current ( I K ) was investigated in isolated embryonic rat sensory neurones using the whole-cell patch-clamp recording technique. Exposure to 100 μM chlorophenylthio-adenosine cyclic 3′,5′-monophosphate (cpt-cAMP) or 1 μM PGE 2 caused a slow suppression of the whole-cell I K by 34 and 36 %, respectively (measured after 20 min), without a shift in the voltage dependence of activation for this current. Neither of these agents altered the shape of the voltage-dependent inactivation curve indicating that the suppression of I K did not result from alterations in the inactivation properties. To determine whether the PGE 2 -mediated suppression of I K depended on activation of the cAMP pathway, cells were exposed to this prostanoid in the presence of the protein kinase A (PKA) inhibitor, PKI. The PGE 2 -induced suppression of I K was prevented by PKI. In the absence of PGE 2 , PKI had no significant effect on the magnitude of I K . Results obtained from protocols using different conditioning prepulse voltages indicated that the extent of cpt-cAMP- and PGE 2 -mediated suppression of I K was independent of the prepulse voltage. The subtraction of control and treated currents revealed that the cpt-cAMP- and PGE 2 -sensitive currents exhibited little time-dependent inactivation. Taken together, these results suggest that the modulated currents may be delayed rectifier-like I K . Exposure to the inhibitors of I K , tetraethylammonium (TEA) or 4-aminopyridine (4-AP), reduced the control current elicited by a voltage step to +60 mV by 40-50 %. In the presence of 10 mM TEA, treatment with cpt-cAMP did not result in any further inhibition of I K . In contrast, cpt-cAMP reduced I K by an additional 25-30 % in the presence of 1 mM 4-AP. This effect was independent of the conditioning prepulse voltage. These results establish that PGE 2 inhibits an outward I K in sensory neurones via activation of PKA and are consistent with the idea that the PGE 2 -mediated sensitization of sensory neurones results, in part, from an inhibition of delayed rectifier-like I K .