Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms

Chen, Lu; Chetkovich, Dane M.; Petralia, Ronald S.; Sweeney, Neal; Kawasaki, Yoichi; Wenthold, Robert J.; Bredt, David S.; Nicoll, Roger A.

doi:10.1038/35050030

Cited by 888 publications

(1,067 citation statements)

References 36 publications

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“…1G-I), confirming that this major synaptic protein of the excitatory post-synaptic density was appropriately sorted to the plasma membrane of cortical pyramidal neurons in culture. Furthermore, PSD-95 is known to associate directly with NMDA ionotropic glutamate receptors (NMDA-R) and indirectly with AMPA ionotropic glutamate receptors (AMPA-R) via stargazin (Kornau et al, 1995;Chen et al, 2000;El-Husseini et al, 2000;Chetkovich et al, 2002;Choi et al, 2002;Schnell et al, 2002), and has been shown to directly interact with the 5-HT 2A receptor (Xia et al, 2003). As expected, PSD-95 in cultured neurons co-localized with NMDA receptors (data not shown) and 5-HT 2A receptors (Fig.…”

Section: Resultssupporting

confidence: 65%

The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro

et al. 2003

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Section: Resultssupporting

confidence: 65%

The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro

et al. 2003

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“…The stargazer mouse has a mutation in Cacng2 that alters the function of Ca v 2.1 and Ca v 2.2 77 and modifies the cell surface expression of AMPA receptors. 78 The mutation in the lethargic mouse interferes with the ␤ 4 subunit modulatory action on the ␣ 1 subunit Ca v 2.1 and Ca v 2.2 although some compensatory subunit insertions ("reshuffling") may occur. 79 In ducky mice, the gene for the ␣2-␦-2 subunit is mutated, and this also alters the function of the Ca v 2.1/2.2 channels.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Whether PSD-95 is responsible for positioning native NMDA receptors at synapses in vivo is an open question, but it is clear that the protein can function as an organizing scaffold that tethers other components to the receptors (Tomita et al, 2001;Hung and Sheng, 2002). A different protein, stargazin, has been shown to play an essential role in targeting AMPA receptors to the neuronal surface and linking the receptors via PSD-95 to synaptic sites on cerebellar granule cells (Chen et al, 2001).…”

Section: Localization Of Nicotinic Receptors On Neuronsmentioning

confidence: 99%

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

2002

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Nicotinic receptors are cation-ion selective ligand-gated ion channels that are expressed throughout the nervous system. Most have significant calcium permeabilities, enabling them to regulate calcium-dependent events. One of the most abundant is a species composed of the ␣7 gene product and having a relative calcium permeability equivalent to that of NMDA receptors. The ␣7-containing receptors can be found presynaptically where they modulate transmitter release, and postsynaptically where they generate excitatory responses. They can also be found in perisynaptic locations where they modulate other inputs to the neuron and can activate a variety of downstream signaling pathways. The effects the receptors produce depend critically on the sites at which they are clustered. Instructive preparations for examining ␣7-containing receptors are the rat hippocampus, where they are thought to play a modulatory role, and the chick ciliary ganglion, where they participate in throughput transmission as well as regulatory signaling. Relatively high levels of ␣7-containing receptors are found in the two preparations, and the receptors display a variety of synaptic options and functions in the two cases. Progress is starting to be made in understanding the mechanisms responsible for localizing the receptors at specific sites and in identifying components tethered in the vicinity of the receptors that may facilitate signal transduction and downstream signaling.

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Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms

Cited by 888 publications

References 36 publications

The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro

The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro

Molecular Targets for Antiepileptic Drug Development

Nicotinic α7 receptors: Synaptic options and downstream signaling in neurons

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