Identification of signal transduction cascades involved in long-lasting potentiation of inhibitory synapses

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In cerebellar Purkinje cells, GABAergic inhibitory synaptic transmission undergoes long-lasting "rebound potentiation" following activation of excitatory climbing fiber iputs. Rebound potentiation is triggered by a climbing fiber-induced transient elevation of intracellular Ca^<2+> concentration, and is expressed as a long-lasting increase of postsynaptic GABA_A receptor sensitivity. In the present series of study, I found that inhibitors of the Ca^<2+>/calmodulin-dependent kinase II (CaM-KII) signal transduction pathway effectively block the induction of rebound potentiation. A non-selective protein kinase inhibitor, staurosporine, effectively blocked the induction of rebound potentiation. A calmodulin antagonist, calmidazolium, and a CaM-KII antagonist, KN-62, effectively blocked rebound potentiation, when they were applied extracellularly prior to and during Ca^<2+> channel activation. On the other hand, these antagonists had no effects on the once established rebound potentiation. … More Intracellular application of a peptide antagonist of CaM-KII also blocked the induction of rebound potentiation. These inhibitors had no effects on voltage-gated Ca^<2+> channel currents or on the basal inhibitory transmission itself. Furthermore, intracellular injection of active CaM-KII and application of a phosphatase inhibitor, calyculin A,induced enhancement of GABA_A receptor-mediated currents. These results strongly suggest that RP involves CaM-KII-mediated protein phosphorylation. The functional state of GABA_A receptors may be dependent on the balance between the phosphorylation by CaM-KII and the dephosphorylation by protein phosphatases.I did not obtain the results that support involvement of other protein kinase cascades in rebound potentiation. As far as I examined, inhibitors of protein kinase A,protein kinase C and protein kinase G had no significant effects on rebound potentiation. The issues of involvement of these protein kinase cascades will be further studied using gene knockout mice. Less