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

1. 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. 2. Exposure to 100 mu M chlorophenylthio-adenosine cyclic 3',5'-monophosphate (cpt-cAMP) or 1 mu M 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. 3. 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. 4. 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. 5. 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. 6. 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.