Activation of ryanodine receptors is required for PKA‐mediated downregulation of A‐type K + channels in rat hippocampal neurons

A‐type K + channels (I A channels) contribute to learning and memory mechanisms by regulating neuronal excitabilities in the CNS, and their expression level is targeted by Ca 2+ influx via synaptic NMDA receptors (NMDARs) during long‐term potentiation (LTP). However, it is not clear how local synaptic Ca 2+ changes induce I A downregulation throughout the neuron, extending from the active synapse to the soma. In this study, we tested if two major receptors of endoplasmic reticulum (ER), ryanodine (RyRs), and IP 3 (IP 3 R) receptors, are involved in Ca 2+ ‐mediated I A downregulation in cultured hippocampal neurons of rats. The downregulation of I A channels was induced by doubling the Ca 2+ concentration in culture media (3.6 mM for 24 hrs) or treating with glycine (200 μM for 3 min) to induce chemical LTP (cLTP), and the changes in I A peaks were measured electrophysiologically by a whole‐cell patch. We confirmed that Ca 2+ or glycine treatment significantly reduced I A peaks and that their effects were abolished by blocking NMDARs or voltage‐dependent Ca 2+ channels (VDCCs). In this cellular processing, blocking RyRs (by ryanodine, 10 μM) but not IP 3 Rs (by 2APB, 100 μM) completely abolished I A downregulation, and the LTP observed in hippocampal slices was more diminished by ryanodine rather than 2APB. Furthermore, blocking RyRs also reduced Ca 2+ ‐mediated PKA activation, indicating that sequential signaling cascades, including the ER and PKA, are involved in regulating I A downregulation. These results strongly suggest a possibility that RyR contribution and mediated I A downregulation are required to regulate membrane excitability as well as synaptic plasticity in CA3‐CA1 connections of the hippocampus. © 2017 Wiley Periodicals, Inc.