Two different ionotropic receptors are activated by ATP in rat microglia.

1. Our aim was to assess whether ATP-induced inward currents in microglia are due to a single or more than one purinergic receptor. The ATP dose-response curve showed two components, whose presence might be due to the activation of high and low affinity receptors. 2. The P2Z/P2X7 specific receptor agonist benzoylbenzoyl-ATP (Bz-ATP) and some P2 receptor agonists were tested. The rank order of potency was Bz-ATP >> ATP = 2-methylthio-ATP (2-MeSATP) > alpha, beta-methylene ATP (alpha,beta-meATP) >= ADP. beta, gamma-MethyleneATP (beta,gamma-meATP), UTP and adenosine were ineffective. 3. The non-specific P2 receptor antagonist suramin antagonized by 92 +/- 2 % the inward current induced by 100 microM ATP, and by 51 +/- 8 and 68 +/- 6 % those induced by 3 mM ATP and 100 microM Bz-ATP, respectively. The P2Z/P2X7 antagonist oxidized ATP (oATP) almost abolished the inward current induced by 3 mM ATP or Bz-ATP, but was ineffective against 100 microM ATP. 4. Inward currents induced by low ATP concentrations (<= 100 microM) were generally followed by an almost complete and irreversible desensitization, while those elicited by ATP >= 1 mM showed only a partial decline. Interestingly, the inward current induced by 100 microM 2-MeSATP showed a large desensitization, while that induced by Bz-ATP did not. 5. In voltage-ramp experiments, the 100 microM ATP-induced current exhibited a slight inward rectification more visible at negative potentials, while the 3 mM ATP-induced current did not. 6. ATP induced a fast and large increase in [Ca2+] that promptly recovered in the continuous presence of low ATP doses, but did not recover in high ATP doses. As with desensitization, the response to Bz-ATP mimicked that of high doses of ATP. 7. When Ca2+ mobilization due to P2Y receptors was blocked by thapsigargin-induced Ca2+ depletion or by pertussis toxin treatment, 10 microM ATP was still able to induce a Ca2+ transient, which represented the contribution of the Ca2+ influx induced by P2X receptors 8. In conclusion, the inward currents and a fraction of the Ca2+ transients induced by ATP in microglia are due to at least two ATP-sensitive receptor channel types, whose different properties and sensitivity to ATP may be associated with different functional roles.