Protein kinases and phosphatase inhibitors mediating long-term desensitization of glutamate receptors in cerebellar Purkinje cells.

Long-term desensitization of the AMPA-selective glutamate receptors in Purkinje cells was examined in rat cerebellar slices by means of the wedge recording method. It was not induced by application of AMPA alone, but occurred regularly when slices were conditioned by perfusion with 0.5 mM 8-bromo-cGMP (but not cAMP derivatives) or the protein phosphatase inhibitors, okadaic acid and calyculin A. Phorbol esters also showed a similar effect. The 8-bromo-cGMP desensitization was antagonized by KT5823, an inhibitor of protein kinase G, while the effect of calyculin A was inhibited by polymyxin B, H-7, or K252a. These results suggest that AMPA receptors are persistently desensitized due to concerted action of both an agonist and an enzymatic system involving protein kinases G and C and a protein phosphatase inhibitor.