1459 0364-3190/03/1000–1459/0 © 2003 Plenum Publishing Corporation Neurochemical Research, Vol. 28, No. 10, October 2003 (© 2003), pp. 1459–1473 INTRODUCTION Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Glutamate is the agonist of two distinct categories of glutamate receptors, metabotropic glutamate receptors and ionotropic glutamate receptors. Ionotropic glutamate receptors have been divided in three classes, according to their pharmaco- logical, molecular, and electrophysiological properties: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors (1,2). Binding of synaptically released glutamate to ionotropic glutamate receptors produces a depolarization Regulation of AMPA Receptor Activity, Synaptic Targeting and Recycling: Role in Synaptic Plasticity* André R. Gomes, 1,2 Susana S. Correia, 1,3 Ana Luísa Carvalho, 1,2 and Carlos B. Duarte 1,2 (Accepted February 28, 2003) The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors for the neuro- transmitter glutamate are oligomeric structures responsible for most fast excitatory responses in the central nervous system. The activity of AMPA receptors can be directly regulated by protein phosphorylation, which may also affect the interaction with intracellular proteins and, conse- quently, their recycling and localization to defined postsynaptic sites. This review focuses on recent advances in understanding the dynamic regulation of AMPA receptors, on a short- and long-term basis, and its implications in synaptic plasticity. KEY WORDS: Glutamate receptors; AMPA receptors; synaptic plasticity; protein phosphorylation; endocy- tosis; synaptic targeting. * Special issue dedicated to Dr. Arsélio Pato de Carvalho. 1 Center for Neuroscience and Cell Biology, University of Coimbra. 2 Department of Zoology, University of Coimbra. 3 Department of Biochemistry, University of Coimbra, Coimbra, Portugal. 4 Address reprint requests to: Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal. Tel: +351 239 480209; Fax: +351 239 822776; E-mail: cbduarte@ci.uc.pt of the postsynaptic region. Each class of receptors plays different roles in synaptic transmission. AMPA receptors mediate the rapid excitatory synaptic transmission (2), whereas kainate receptors regulate neuronal activity pre- dominantly at a presynaptic level (3). NMDA receptors mediate a slower component of excitatory neurotransmis- sion and are blocked by magnesium at resting potential. NMDA receptor activation and subsequent calcium influx are crucial in the induction of specific forms of synaptic plasticity, such as long-term potentiation (LTP) and long- term depression (LTD) (2,4). In this review we focus on recent advances in the regulation of AMPA receptors and their role in synaptic plasticity. AMPA receptors are tetrameric structures that combine homologous subunits GluR1 to GluR4 (or GluRA to GluRD) in different stoichiometries to form receptors with distinct properties (1,5). Each monomer carries its own glutamate binding site and contributes with a specific membrane-inserted hydrophobic amino acid sequence to form the cation permeable channel (TM2 region). Besides this hydrophobic sequence, each subunit has three transmembrane segments (TM1, TM3,