Secretory phospholipase A2 (sPLA2) has been reported to modulate agonist and antagonist binding to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Here we report that in hippocampal membranes sPLA2 increases the affinity of [3H]AMPA binding whereas in cortical membranes the affinity of binding is decreased. To test whether these results are due to the interaction of sPLA2 with different AMPA receptor subunits we used membranes from BHK cells expressing homomeric GluR1, GluR2 or GluR4 receptors. Pretreatment with the enzyme had no effect on [3H]AMPA binding to any of the homomeric receptors. We interpret these data to suggest that sPLA2 does not act directly at the AMPA receptor. Instead, sPLA2 may interact with a receptor-associated protein present in brain but not in BHK cells and this interaction may exert different effects in cortex and hippocampus.