Multiple P2X receptors on guinea-pig pelvic ganglion neurons exhibit novelpharmacological properties

1 Application of ATP and alpha,beta -methylene ATP (alpha beta meATP) to vo ltage-clamped guinea-pig pelvic neurons produced three types of inward curr ents. A fast-desensitizing response was present in 5% (25/660) of neurons, 70% gave slowly-desensitizing currents, and the remainder had biphasic resp onses. 2 Slowly-desensitizing responses were characterized pharmacologically. The response to alpha beta meATP 100 muM was 46 +/- 27% (range 0-100%) of that evoked by ATP 100 muM in the same cell. Cross-desensitization indicated the presence of alpha beta meATP-sensitive and -insensitive receptors. 3 The concentration-response curve for alpha beta meATP had an EC50 of 55 m uM, and a Hill coefficient of 0.99, while at the alpha beta meATP-insensiti ve receptor, ATP had an EC50 of 73 muM, With a Hill coefficient of 1.78. 4 The response to apmeATP was blocked by pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS), suramin and Cibacron blue. However, the alpha beta meATP-insensitive receptor was inhibited by PPADS, but not by the othe r two antagonists. 5 2'- (or 3'-) O-trinitrophenyl-ATP was 10 times more potent in inhibiting responses to apmeATP than to ATP (at the alpha beta meATP-insensitive recep tor). 6 Lowering extracellular pH potentiated responses to apmeATP and ATP, while raising pH attenuated them. 7 Co-application of Zn2+ (3-300 muM) inhibited the responses to apmeATP and ATP, with IC50 values of 286 and 60 muM, respectively. 8 In conclusion, unlike rat and mouse pelvic ganglion neurons, which only e xpress P2X(2) homomers, at least three distinct P2X receptors are present i n guinea-pig pelvic neurons, probably homomeric P2X(2), P2X(3) and heterome ric P2X(2/3) receptors. However, some of the novel pharmacological properti es observed suggest that the guinea-pig P2X receptor subtypes may differ fr om their rat orthologues.