||The molecular and cellular mechanisms of learning and memory are the key topics of neuroscience research. Synapses are specialized structures mediating neuron-neuron communication. The strength of synaptic response can be modified during synaptic plasticity. Trafficking of AMPA-type glutamate receptors (AMPARs), the major excitatory neurotransmitter receptors in the brain plays a crucial role in synaptic plasticity. Insertion of additional AMPARs to the postsynaptic membrane will lead to larger response and long-term potentiation, while removal of AMPARs from synapses results in smaller response and long-term depression. There are four AMPAR subunits (GluA1-4) that can differentially combine to form homo- or hetero-tetrameric receptors. Recent studies showed that different AMPAR subunits transport differently and their differential trafficking is important for synaptic plasticity. However, the mechanism underling differential trafficking of AMPAR subunits is not fully understood. To address this question, we searched for proteins that specifically associate with different subunits of AMPARs. We identified G-protein coupled receptor kinase 2 (GRK2) as an intracellular binding partner specific for AMPAR subunit GluA1, but not GluA2 or GluA3. GRK2 is well characterized for its role in the membrane trafficking of G-protein coupled receptors. More interestingly, we found that binding of GRK2 and GluA1 in neurons was regulated by neuronal activity and it played an important role in regulating GluA1 trafficking.