Ca ²⁺ /calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors

TLDR

Long‑term potentiation in hippocampal CA1 depends on Ca²⁺/calmodulin‑kinase II phosphorylation of GluR1 Ser‑831, a postsynaptic mechanism underlying memory and learning. The study aimed to uncover the molecular mechanism by which CaM‑KII potentiates AMPA receptors. Activated CaM‑KII was co‑expressed with GluR1 in HEK‑293 cells, and single‑channel recordings were used to assess conductance states. Co‑expression increased the proportion of high‑conductance states without altering glutamate affinity or gating, showing that CaM‑KII enhances synaptic plasticity by raising single‑channel conductance or recruiting high‑conductance AMPA receptors.

Abstract

The ability of central glutamatergic synapses to change their strength in response to the intensity of synaptic input, which occurs, for example, in long-term potentiation (LTP), is thought to provide a cellular basis for memory formation and learning. LTP in the CA1 field of the hippocampus requires activation of Ca 2+ /calmodulin-kinase II (CaM-KII), which phosphorylates Ser-831 in the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor (AMPA-R), and this activation/phosphorylation is thought to be a postsynaptic mechanism in LTP. In this study, we have identified a molecular mechanism by which CaM-KII potentiates AMPA-Rs. Coexpression in HEK-293 cells of activated CaM-KII with GluR1 did not affect the glutamate affinity of the receptor, the kinetics of desensitization and recovery, channel rectification, open probability, or gating. Single-channel recordings identified multiple conductance states for GluR1, and coexpression with CaM-KII or a mutation of Ser-831 to Asp increased the contribution of the higher conductance states. These results indicate that CaM-KII can mediate plasticity at glutamatergic synapses by increasing single-channel conductance of existing functional AMPA-Rs or by recruiting new high-conductance-state AMPA-Rs.