Separate Paths to the Surface

Abstract

AMPA glutamate receptors (GluR) are hetero-oligomeric proteins and multiple combinations of subunits are expressed in the same neuron. The different combinations have been implicated in different types of neuronal activity, for example, receptors formed from GluR1/GluR2 subunits increase in response to neuronal activity and are important for mediating long-term potentiation, a process implicated in learning and memory. Receptors formed from GluR2/GluR3 subunits are involved in controlling basal neuronal excitability. Shi et al. used cultured neurons and organotypic slice preparations to express various AMPA GluR subunits and modified subunits or portions thereof. The delivery of the proteins was monitored by fusion with green fluorescent protein, the inclusion of a point mutation that altered their electrophysiological properties, or both. Based on the results from expression of the various combinations of proteins, two independent pathways for delivery of the receptors to the cell surface were identified. The GluR1-containing receptors, including GluR1/GluR2 receptors, were not inserted in the plasma membrane unless the synapses were stimulated or unless activated calcium-calmodulin-dependent protein kinase II was also expressed. GluR2 homo-oligomers or GluR2/GluR3 hetero-oligomers were constitutively inserted into the membrane, and the endogenous receptors were continuously endocytosed. Trafficking of GluR-containing receptors depended on the binding domain for PDZ group 1 proteins, and trafficking of the GluR2/GluR2 or GluR2/GluR3 receptors depended on the GluR2 PDZ group II binding domain and interaction with N-ethylmaleimide-sensitive factor (NSF). The independence of the trafficking pathways was confirmed by expression of the COOH-domains of GluR1 or GluR2, which showed only selective inhibition of the cognate receptor's delivery. These two independently regulated pathways contribute to the control of synaptic activity.S.-H. Shi, Y. Hayashi, J. A. Esteban, R. Malinow, Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331-343 (2001). [Online Journal]