Coexpression of P2X(3) and P2X(2) receptor subunits in varying amounts generates heterogeneous populations of P2X receptors that evoke a spectrum of agonist responses comparable to that seen in sensory neurons

Using voltage-clamp procedures on Xenopus oocytes, agonist-evoked ionic cur rents by P2X receptors resulting from the coexpression of P2X(2) and P2X(3) subunits were compared against the agonist responses of homomeric P2X(2) a nd P2X(3) receptors. With the quantity of P2X(3) mRNA kept constant and qua ntity of P2X(2) mRNA progressively increased, expressed P2X receptors chang ed from a P2X(3)-like receptor to a P2X(2)-like receptor. In all cases, how ever, agonist-evoked responses comprised biphasic (fast and slow) currents- the former showing the properties of P2X(3) receptors and latter consistent with the presence of P2X(2) and P2X(2/3) receptors. Using desensitization procedures, the P2X(3)-like fast current was selectively removed to allow t he slow current to be studied in isolation. P2X(2/3) receptors were then ch aracterized by slowly inactivating inward currents that were reproducible w ithin 30 s of washout and whose pharmacological profile [selective agonists , Ap(5)A > alpha,beta -methylene ATP >> beta, gamma -methylene ATP > UTP; a ntagonists, TNP-ATP >> suramin greater than or equal to Reactive blue-2 (RB -2)] contrasted with the profile of P2X(2) receptors (Ap(5)A, alpha,beta -m ethylene ATP, beta, gamma -methylene ATP, and UTP inactive; antagonists, RB -2. TNP-ATP. suramin). Thus, our experiments reveal that coexpression of tw o P2X subunits, which of themselves can generate functional homomeric recep tors, results in a complex population of heterogeneous P2X receptors-in thi s case P2X(2), P2X(3), and P2X(2/3) receptors. Depending on the relative le vels of P2X subunit coexpression, the operational profile of the resultant P2X receptors can change from one phenotype to another. This spectrum may e xplain the variability of agonist responses in small sensory neurons that a lso express P2X(2) and P2X(3) subunits in different amounts.