AMPA-selective glutamate receptors are ligand-gated cation channels that mediate fast excitatory neurotransmission in the brain and thus mediate many aspects of brain function including cognition, movement, learning and memory. The function and number of postsynaptic AMPA receptors is dynamically regulated by a number of cellular mechanisms to control synaptic strength, a key feature of cellular models of learning and memory such as long-term potentiation. The function, trafficking and synaptic signaling of AMPA receptors containing the GluA1 subunit is tightly regulated by phosphorylation. Ca2+/calmodulin-dependent kinase II (CaMKII) phosphorylates the GluA1 AMPA receptor subunit at Ser831 to increase single-channel conductance. We show that CaMKII increases the conductance of native AMPA receptors in mouse hippocampal neurons through phosphorylation of Ser831 located in the intracellular C-terminal domain. Dissection of the molecular mechanism underlying CamKII modulation of conductance reveal that transmembrane AMPA receptor regulatory proteins (TARPs) play an critical role for allowing for phospho-Ser831 to increase conductance of heteromeric GluA1-GluA2 receptors; a main AMPA receptor subtype in hippocampal neurons. Phosphorylation of Ser831 increases the efficiency with which each subunit can activate, thereby increasing the likelihood that more receptor subunits will be simultaneously activated during gating. The molecular basis for this regulation is currently unknown. Present work evaluating the mechanism by which GluA1 phosphorylation influences AMPA receptor function include studies of intra- or interprotein interactions in AMPA receptor C-terminal that may be modulated by TARPs and GluA1 phosphorylation.