The regulated trafficking of neurotransmitter receptors at synapses is critical for synaptic function and plasticity. However, the molecular machinery that controls active transport of receptors into synapses is largely unknown. We found that, in rat hippocampus, the insertion of AMPA receptors (AMPARs) into spines during synaptic plasticity requires a specific motor protein, which we identified as myosin Va. We found that myosin Va associates with AMPARs through its cargo binding domain. This interaction was enhanced by active, GTP-bound Rab11, which is also transported by the motor protein. Myosin Va mediated the CaMKII-triggered translocation of GluR1 receptors from the dendritic shaft into spines, but it was not required for constitutive GluR2 trafficking. Accordingly, myosin Va was specifically required for long-term potentiation, but not for basal synaptic transmission. In summary, we identified the specific motor protein and organelle acceptor that catalyze the directional transport of AMPARs into spines during activity-dependent synaptic plasticity.
Central noradrenergic signalling mediates arousal and facilitates learning through unknown molecular mechanisms. Here, we show that the b 2 -adrenergic receptor (b 2 AR), the trimeric G s protein, adenylyl cyclase, and PKA form a signalling complex with the AMPA-type glutamate receptor subunit GluR1, which is linked to the b 2 AR through stargazin and PSD-95 and their homologues. Only GluR1 associated with the b 2 AR is phosphorylated by PKA on b 2 AR stimulation. Peptides that interfere with the b 2 ARGluR1 association prevent this phosphorylation of GluR1. This phosphorylation increases GluR1 surface expression at postsynaptic sites and amplitudes of EPSCs and mEPSCs in prefrontal cortex slices. Assembly of all proteins involved in the classic b 2 AR-cAMP cascade into a supramolecular signalling complex and thus allows highly localized and selective regulation of one of its major target proteins.
Myosin V motors mediate cargo transport; however, the identity of neuronal molecules transported by these proteins remains unknown. Here we show that myosin Vb is expressed in several neuronal populations and associates with the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor subunit GluR1. In developing hippocampal neurons, expression of the tail domain of myosin Vb, but not myosin Va, enhanced GluR1 accumulation in the soma and reduced its surface expression. These changes were accompanied by reduced GluR1 clustering and diminished frequency of excitatory but not inhibitory synaptic currents. Similar effects were observed upon expression of full-length myosin Vb lacking a C-terminal region required for binding to the small GTPase Rab11. In contrast, mutant myosin Vb did not change the localization of several other neurotransmitter receptors, including the glutamate receptor subunit NR1. These results reveal a novel mechanism for the transport of a specific glutamate receptor subunit in neurons mediated by a member of the myosin V family.Proper sorting and transport of excitatory neurotransmitter receptors and associated proteins is essential for neuronal activity and plasticity. Recent studies have identified several proteins that regulate clustering of neurotransmitter receptors at the synapse (1). However, it remains unknown what proteins mediate sorting and delivery of receptors from the soma to postsynaptic sites. Molecular motors that regulate cargo trafficking on both actin filaments and microtubules have been implicated in initial transport and delivery to specific subcellular sites (2, 3). In particular, class V of unconventional myosins is actin-based motors thought to regulate trafficking of organelles and associated proteins in neuronal cells (2, 4).Three known members of the myosin V family have been detected in brain extracts. The most studied member, myosin Va, is widely expressed in the brain (5). Dilute mice, which possess mutation in the myosin Va gene, suffer from impaired melanosome transport and severe seizures and die within 2-3 weeks after birth (6). These observations suggest that alteration in the transport of important yet unknown cargos contributed to the observed defects in neuronal function. In neurons, myosin Va is enriched at the postsynaptic density (PSD) 4 of excitatory synapses (7) and associates with the scaffolding guanylate kinase domain-associated protein through interaction with the dynein light chain (8). The association of guanylate kinase domain-associated protein with the postsynaptic density protein-95 (PSD-95), a protein involved in glutamate receptor clustering, may functionally couple these proteins to myosin Va (1, 9).Myosin Vb and myosin Vc are two additional members of the myosin V family that are also expressed in the brain; however, their exact localization in neurons remains unclear (10, 11). All of these motors share ϳ42% identity and contain a conserved N-terminal motor domain followed by a coiled-coil region and a globular C-termi...
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