Cerebellar Kainate Receptor-Mediated Facilitation of Glutamate Release Requires Ca(2+)-Calmodulin and PKA

We elucidated the mechanisms underlying the kainate receptor (KAR)-mediated facilitatory modulation of synaptic transmission in the cerebellum. In cerebellar slices, KA (3 μM) increased the amplitude of evoked excitatory postsynaptic currents (eEPSCs) at synapses between axon terminals of parallel fibers (PF) and Purkinje neurons. KA-mediated facilitation was antagonized by NBQX under condition where AMPA receptors were previously antagonized. Inhibition of protein kinase A (PKA) suppressed the effect of KA on glutamate release, which was also obviated by the prior stimulation of adenylyl cyclase (AC). KAR-mediated facilitation of synaptic transmission was prevented by blocking Ca(2+) permeant KARs using philanthotoxin. Furthermore, depletion of intracellular Ca(2+) stores by thapsigargin, or inhibition of Ca(2+)-induced Ca(2+)-release by ryanodine, abrogated the synaptic facilitation by KA. Thus, the KA-mediated modulation was conditional on extracellular Ca(2+) entry through Ca(2+)-permeable KARs, as well as and mobilization of Ca(2+) from intracellular stores. Finally, KAR-mediated facilitation was sensitive to calmodulin inhibitors, W-7 and calmidazolium, indicating that the increased cytosolic [Ca(2+)] sustaining KAR-mediated facilitation of synaptic transmission operates through a downstream Ca(2+)/calmodulin coupling. We conclude that, at cerebellar parallel fiber-Purkinje cell synapses, presynaptic KARs mediate glutamate release facilitation, and thereby enhance synaptic transmission through Ca(2+)-calmodulin dependent activation of adenylyl cyclase/cAMP/protein kinase A signaling.