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Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins.

Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS - J. Cell Biol. (2003)

Bottom Line: Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins.Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors.These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP-AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

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γ-4 is expressed in glial cells in adult rat. In situ hybridization (A, B, E, and F) and immunocytochemistry (C, D, G, and H) show that γ-4 but not stargazin (STG) is expressed in glial cells. (A) In cerebellum, stargazin mRNA is expressed in granule cells (GC), Purkinje cells (PC; arrowheads), and in interneurons (arrows) in molecular layer (ML). (B) In contrast, γ-4 mRNA occurs in a diffuse band along the Purkinje cell layer that reflects expression in Bergmann glia (BG) as indicated in C by immunostaining of their apical processes in the molecular layer (arrows). Scattered cells in cerebellum showing γ-4 mRNA expression (B, arrows) are glia, since immunostaining shows their fibrous star-shaped morphology (D, arrows). (E) In neocortex, stargazin mRNA is expressed in neurons of cerebral cortex (Cx), granule cells of dentate gyrus (DG), and pyramidal cells of the hippocampus (CA). Stargazin is also expressed in interneurons of hilus of dentate gyrus (arrows) and in stratum oriens (arrowheads) and stratum radiatum. (F) In contrast, γ-4 mRNA occurs in scattered cells throughout cerebral cortex (Cx), corpus callosum (CC), and hippocampus (arrows) that resemble glia as detected by immunocytochemistry (G and H).
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fig3: γ-4 is expressed in glial cells in adult rat. In situ hybridization (A, B, E, and F) and immunocytochemistry (C, D, G, and H) show that γ-4 but not stargazin (STG) is expressed in glial cells. (A) In cerebellum, stargazin mRNA is expressed in granule cells (GC), Purkinje cells (PC; arrowheads), and in interneurons (arrows) in molecular layer (ML). (B) In contrast, γ-4 mRNA occurs in a diffuse band along the Purkinje cell layer that reflects expression in Bergmann glia (BG) as indicated in C by immunostaining of their apical processes in the molecular layer (arrows). Scattered cells in cerebellum showing γ-4 mRNA expression (B, arrows) are glia, since immunostaining shows their fibrous star-shaped morphology (D, arrows). (E) In neocortex, stargazin mRNA is expressed in neurons of cerebral cortex (Cx), granule cells of dentate gyrus (DG), and pyramidal cells of the hippocampus (CA). Stargazin is also expressed in interneurons of hilus of dentate gyrus (arrows) and in stratum oriens (arrowheads) and stratum radiatum. (F) In contrast, γ-4 mRNA occurs in scattered cells throughout cerebral cortex (Cx), corpus callosum (CC), and hippocampus (arrows) that resemble glia as detected by immunocytochemistry (G and H).

Mentions: To assess the regional distribution of TARPs in brain, we generated and affinity purified antipeptide antibodies specific for each isoform. Western blotting on protein extracts from cerebellum, cerebral cortex, hippocampus, and olfactory bulb showed that each TARP was enriched in a different brain region. Highest levels of γ-2 occur in cerebellum, γ-3 in cerebral cortex, γ-4 in olfactory bulb, and γ-8 in hippocampus (Fig. 2 A). To determine the cellular distribution of the TARPs, we performed in situ hybridization on sagittal and coronal sections of adult rat brain with 35S-labeled antisense probes, which revealed distinctive patterns for each TARP (Fig. 2, B and C). As previously reported, stargazin/γ-2 mRNA is discretely expressed in specific neuronal populations in numerous brain regions and occurs at highest levels in cerebellum but also occurs in cerebral cortex, hippocampus, and facial nerve nucleus. At higher power, images show that stargazin in hippocampus occurs both in pyramidal cells and interneurons (Fig. 3 E), and γ-3, also expressed exclusively in neuronal cells, occurs at highest levels in cerebral cortex (Fig. 2, B and C). By contrast, γ-4 is expressed both in specific neuronal populations, such as the caudate putamen, but also appear in nonneuronal cells as suggested by expression in white matter of the corpus callosum (Fig. 2, B and C).


Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins.

Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS - J. Cell Biol. (2003)

γ-4 is expressed in glial cells in adult rat. In situ hybridization (A, B, E, and F) and immunocytochemistry (C, D, G, and H) show that γ-4 but not stargazin (STG) is expressed in glial cells. (A) In cerebellum, stargazin mRNA is expressed in granule cells (GC), Purkinje cells (PC; arrowheads), and in interneurons (arrows) in molecular layer (ML). (B) In contrast, γ-4 mRNA occurs in a diffuse band along the Purkinje cell layer that reflects expression in Bergmann glia (BG) as indicated in C by immunostaining of their apical processes in the molecular layer (arrows). Scattered cells in cerebellum showing γ-4 mRNA expression (B, arrows) are glia, since immunostaining shows their fibrous star-shaped morphology (D, arrows). (E) In neocortex, stargazin mRNA is expressed in neurons of cerebral cortex (Cx), granule cells of dentate gyrus (DG), and pyramidal cells of the hippocampus (CA). Stargazin is also expressed in interneurons of hilus of dentate gyrus (arrows) and in stratum oriens (arrowheads) and stratum radiatum. (F) In contrast, γ-4 mRNA occurs in scattered cells throughout cerebral cortex (Cx), corpus callosum (CC), and hippocampus (arrows) that resemble glia as detected by immunocytochemistry (G and H).
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Related In: Results  -  Collection

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fig3: γ-4 is expressed in glial cells in adult rat. In situ hybridization (A, B, E, and F) and immunocytochemistry (C, D, G, and H) show that γ-4 but not stargazin (STG) is expressed in glial cells. (A) In cerebellum, stargazin mRNA is expressed in granule cells (GC), Purkinje cells (PC; arrowheads), and in interneurons (arrows) in molecular layer (ML). (B) In contrast, γ-4 mRNA occurs in a diffuse band along the Purkinje cell layer that reflects expression in Bergmann glia (BG) as indicated in C by immunostaining of their apical processes in the molecular layer (arrows). Scattered cells in cerebellum showing γ-4 mRNA expression (B, arrows) are glia, since immunostaining shows their fibrous star-shaped morphology (D, arrows). (E) In neocortex, stargazin mRNA is expressed in neurons of cerebral cortex (Cx), granule cells of dentate gyrus (DG), and pyramidal cells of the hippocampus (CA). Stargazin is also expressed in interneurons of hilus of dentate gyrus (arrows) and in stratum oriens (arrowheads) and stratum radiatum. (F) In contrast, γ-4 mRNA occurs in scattered cells throughout cerebral cortex (Cx), corpus callosum (CC), and hippocampus (arrows) that resemble glia as detected by immunocytochemistry (G and H).
Mentions: To assess the regional distribution of TARPs in brain, we generated and affinity purified antipeptide antibodies specific for each isoform. Western blotting on protein extracts from cerebellum, cerebral cortex, hippocampus, and olfactory bulb showed that each TARP was enriched in a different brain region. Highest levels of γ-2 occur in cerebellum, γ-3 in cerebral cortex, γ-4 in olfactory bulb, and γ-8 in hippocampus (Fig. 2 A). To determine the cellular distribution of the TARPs, we performed in situ hybridization on sagittal and coronal sections of adult rat brain with 35S-labeled antisense probes, which revealed distinctive patterns for each TARP (Fig. 2, B and C). As previously reported, stargazin/γ-2 mRNA is discretely expressed in specific neuronal populations in numerous brain regions and occurs at highest levels in cerebellum but also occurs in cerebral cortex, hippocampus, and facial nerve nucleus. At higher power, images show that stargazin in hippocampus occurs both in pyramidal cells and interneurons (Fig. 3 E), and γ-3, also expressed exclusively in neuronal cells, occurs at highest levels in cerebral cortex (Fig. 2, B and C). By contrast, γ-4 is expressed both in specific neuronal populations, such as the caudate putamen, but also appear in nonneuronal cells as suggested by expression in white matter of the corpus callosum (Fig. 2, B and C).

Bottom Line: Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins.Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors.These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
Functional expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, gamma-3, gamma-4, and gamma-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP-AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.

Show MeSH
Related in: MedlinePlus