The study investigates the molecular mechanism by which Ca2+/calmodulin-kinase II (CaM-KII) enhances the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, which are crucial for long-term potentiation (LTP) in the hippocampus. Coexpression of activated CaM-KII with GluR1 in HEK-293 cells did not affect glutamate affinity, desensitization, recovery, channel rectification, open probability, or gating. However, single-channel recordings revealed multiple conductance states for GluR1, and coexpression with CaM-KII or mutation of Ser-831 to Asp increased the contribution of higher conductance states. This indicates that CaM-KII can enhance synaptic plasticity by increasing the single-channel conductance of existing AMPA receptors or recruiting new high-conductance-state receptors. The results provide a molecular basis for how CaM-KII mediates LTP by increasing the total current through AMPA receptors during their activation.The study investigates the molecular mechanism by which Ca2+/calmodulin-kinase II (CaM-KII) enhances the conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, which are crucial for long-term potentiation (LTP) in the hippocampus. Coexpression of activated CaM-KII with GluR1 in HEK-293 cells did not affect glutamate affinity, desensitization, recovery, channel rectification, open probability, or gating. However, single-channel recordings revealed multiple conductance states for GluR1, and coexpression with CaM-KII or mutation of Ser-831 to Asp increased the contribution of higher conductance states. This indicates that CaM-KII can enhance synaptic plasticity by increasing the single-channel conductance of existing AMPA receptors or recruiting new high-conductance-state receptors. The results provide a molecular basis for how CaM-KII mediates LTP by increasing the total current through AMPA receptors during their activation.