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

A. R. Evans *, M. R. Vasko *¹ and G. D. Nicol *

The role of the cyclic AMP (cAMP) transduction cascade in mediating the prostaglandin E₂ (PGE₂)-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 PGE₂ 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 PGE₂-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 PGE₂-induced suppression of I_K was prevented by PKI. In the absence of PGE₂, 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 PGE₂-mediated suppression of I_K was independent of the prepulse voltage. The subtraction of control and treated currents revealed that the cpt-cAMP- and PGE₂-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 PGE₂ inhibits an outward I_K in sensory neurones via activation of PKA and are consistent with the idea that the PGE₂-mediated sensitization of sensory neurones results, in part, from an inhibition of delayed rectifier-like I_K.

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