TY - JOUR T1 - Frequency-Dependent Inactivation of Mammalian A-Type K<sup>+</sup> Channel K<sub>V</sub>1.4 Regulated by Ca<sup>2+</sup>/Calmodulin-Dependent Protein Kinase JF - The Journal of Neuroscience JO - J. Neurosci. SP - 3379 LP - 3391 DO - 10.1523/JNEUROSCI.17-10-03379.1997 VL - 17 IS - 10 AU - Jochen Roeper AU - Christoph Lorra AU - Olaf Pongs Y1 - 1997/05/15 UR - http://www.jneurosci.org/content/17/10/3379.abstract N2 - Ca2+/calmodulin dependent protein kinase (CaMKII) and protein phosphatase 2B (calcineurin) are key enzymes in the regulation of synaptic strength, controlling the phosphorylation status of pre- and postsynaptic target proteins. Here, we show that the inactivation gating of the Shaker-related fast-inactivating KV channel, Kv1.4 is controlled by CaMKII and the calcineurin/inhibitor-1 protein phosphatase cascade. CaMKII phosphorylation of an amino-terminal residue of KV1.4 leads to slowing of inactivation gating and accelerated recovery from N-type inactivated states. In contrast, dephosphorylation of this residue induces a fast inactivating mode of KV1.4 with time constants of inactivation 5 to 10 times faster compared with the CaMKII-phosphorylated form. Dephosphorylated KV1.4 channels also display slowed and partial recovery from inactivation with increased trapping of KV1.4 channels in long-absorbing C-type inactivated states. In consequence, dephosphorylated KV1.4 displays a markedly increased tendency to undergo cumulative inactivation during repetitive stimulation. The balance between phosphorylated and dephosphorylated KV1.4 channels is regulated by changes in intracellular Ca2+ concentration rendering KV1.4 inactivation gating Ca2+-sensitive. The reciprocal CaMKII and calcineurin regulation of cumulative inactivation of presynaptic KV1.4 may provide a novel mechanism to regulate the critical frequency for presynaptic spike broadening and induction of synaptic plasticity. ER -