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

2003 ◽  
Vol 161 (4) ◽  
pp. 805-816 ◽  
Author(s):  
Susumu Tomita ◽  
Lu Chen ◽  
Yoshimi Kawasaki ◽  
Ronald S. Petralia ◽  
Robert J. Wenthold ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Cerebellar Granule Cells ◽  
Surface Expression ◽  
Brain Regions ◽  
Regulatory Proteins ◽  
General Role ◽  
Receptor Complexes

Functional expression of α-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, γ-3, γ-4, and γ-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.

Comparison of the Effects of Convulsant and Depressant Barbiturate Stereoisomers on AMPA-type Glutamate Receptors

1999 ◽  
Vol 90 (6) ◽  
pp. 1704-1713. ◽  
Author(s):  
Yoshinori Kamiya ◽  
Tomio Andoh ◽  
Ryosuke Furuya ◽  
Satoshi Hattori ◽  
Itaru Watanabe ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glutamate Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Dependent Manner ◽  
Induced Current ◽  
Gaba A ◽  
The Central Nervous System

Background Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. Method The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. Results Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. Conclusions Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

scholarly journals Real-time imaging of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) movements in neurons

2003 ◽  
Vol 31 (4) ◽  
pp. 880-884 ◽  
Author(s):  
P. Perestenko ◽  
M.C. Ashby ◽  
J.M. Henley
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Surface Expression ◽  
Protein Protein Interactions ◽  
Acid Receptor ◽  
Excitatory Neurotransmission ◽  
Living Neurons

The mechanisms that regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) synthesis, transport, targeting and surface expression are of fundamental importance for fast excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system. It has become apparent that these control processes involve complex sets of protein–protein interactions and many of the proteins responsible have been identified. We have been working to visualize AMPAR movement in living neurons in order to investigate the effects of blocking protein interactions. Here we outline the approaches used and the results obtained thus far.

scholarly journals Control of AMPA receptor activity by the extracellular loops of auxiliary proteins

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Irene Riva ◽  
Clarissa Eibl ◽  
Rudolf Volkmer ◽  
Anna L Carbone ◽  
Andrew JR Plested
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
De Novo ◽  
Dominant Role ◽  
Mammalian Brain ◽  
Binding Assays ◽  
Receptor Kinetics ◽  
Receptor Complexes ◽  
Extracellular Loops ◽  
Kinetics Of

At synapses throughout the mammalian brain, AMPA receptors form complexes with auxiliary proteins, including TARPs. However, how TARPs modulate AMPA receptor gating remains poorly understood. We built structural models of TARP-AMPA receptor complexes for TARPs γ2 and γ8, combining recent structural studies and de novo structure predictions. These models, combined with peptide binding assays, provide evidence for multiple interactions between GluA2 and variable extracellular loops of TARPs. Substitutions and deletions of these loops had surprisingly rich effects on the kinetics of glutamate-activated currents, without any effect on assembly. Critically, by altering the two interacting loops of γ2 and γ8, we could entirely remove all allosteric modulation of GluA2, without affecting formation of AMPA receptor-TARP complexes. Likewise, substitutions in the linker domains of GluA2 completely removed any effect of γ2 on receptor kinetics, indicating a dominant role for this previously overlooked site proximal to the AMPA receptor channel gate.

Low concentrations of hydrogen sulphide alter monoamine levels in the developing rat central nervous system

1992 ◽  
Vol 70 (11) ◽  
pp. 1515-1518 ◽  
Author(s):  
B. Skrajny ◽  
R. S. Hannah ◽  
S. H. Roth
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Frontal Cortex ◽  
Hydrogen Sulphide ◽  
Chronic Exposure ◽  
Brain Regions ◽  
Target Organs ◽  
Low Concentrations ◽  
The Central Nervous System ◽  
Developing Rat

The central nervous system is one of the primary target organs for hydrogen sulphide (H2S) toxicity; however, there are limited data on the neurotoxic effects of low-dose chronic exposure on the developing nervous system. Levels of serotonin and norepinephrine in the developing rat cerebellum and frontal cortex were determined following chronic exposure to 20 and 75 ppm H2S during perinatal development. Both monoamines were altered in rats exposed to 75 ppm H2S compared with controls; serotonin levels were significantly increased at days 14 and 21 postnatal in both brain regions, and norepinephrine levels were significantly increased at days 7, 14, and 21 postnatal in cerebellum and at day 21 in the frontal cortex. Exposure to 20 ppm H2S significantly increased the levels of serotonin in the frontal cortex at day 21, whereas levels of norepinephrine were significantly reduced in the frontal cortex at days 14 and 21, and at day 14 in the cerebellum.Key words: hydrogen sulphide, monoamines, serotonin, norepinephrine, neurotoxicity.

scholarly journals Neuropathological Findings in a Case of IFIH1-Related Aicardi–Goutières Syndrome

2019 ◽  
Vol 22 (6) ◽  
pp. 566-570
Author(s):  
Ahmed Gilani ◽  
Laura A Adang ◽  
Adeline Vanderver ◽  
Abigail Collins ◽  
BK Kleinschmidt-DeMasters
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Atrophy ◽  
Cardiopulmonary Arrest ◽  
Brain Regions ◽  
Variable Degree ◽  
Expression Data ◽  
Ultrastructural Examination ◽  
The Central Nervous System ◽  
Gross Examination

Aicardi–Goutières syndrome (AGS) is a rare syndrome characterized by calcification, diffuse demyelination, and variable degree of brain atrophy. The syndrome is genetically heterogeneous with mutations in 7 genes, including TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1 (interferon-induced helicase c domain-containing protein 1) associated with the syndrome, so far. These mutations lead to the overproduction of α-interferon within the central nervous system. Mutations in IFIH1 have been recently described in a subset of AGS, with only 1 previous report of neuropathological findings. We report neuropathological findings in a second case of AGS with a known mutation in IFIH1 gene. The patient is a 16-year-old adolescent boy with early-onset symptoms that progressed to profound loss of cognitive and motor functions. The patient experienced sudden cardiopulmonary arrest at the age of 16 years. At autopsy, the cause of death was determined to be pulmonary thromboembolism. Neuropathological examination revealed microcephaly (brain weight: 916 g) with relatively mild brain atrophy on gross examination. Microscopic examination revealed multifocal calcifications limited to small to medium central nervous system arteries (no evidence of calcification in other organs), involving bilateral cerebral cortex, basal ganglia, thalamus, and cerebellum. Ultrastructural examination showed Calcospherules limited to the vessel walls and the perivasulcar area without evidence of neuronal ferrugination or tubuloreticular bodies. The extent of calcifications was variable across different brain regions, resembling findings in previously reported cases and correlated with the extent of IFIH1 protein expression (data derived from Allen Brain Institute). AGS is a rare cause of brain calcifications that can closely mimic congenital and neonatal infections such as Rubella and similar infections.

PVN activation is suppressed by repeated hypoglycemia but not antecedent corticosterone in the rat

2001 ◽  
Vol 281 (5) ◽  
pp. R1426-R1436 ◽  
Author(s):  
Scott B. Evans ◽  
Charles W. Wilkinson ◽  
Kathy Bentson ◽  
Pam Gronbeck ◽  
Aryana Zavosh ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Autonomic Failure ◽  
Brain Activation ◽  
Brain Regions ◽  
Neuroendocrine Response ◽  
Medial Hypothalamus ◽  
Neuroendocrine Responses ◽  
Hypothalamic Activation

The mechanism(s) underlying hypoglycemia-associated autonomic failure (HAAF) are unknown. To test the hypothesis that the activation of brain regions involved in the counterregulatory response to hypoglycemia is blunted with HAAF, rats were studied in a 2-day protocol. Neuroendocrine responses and brain activation (c-Fos immunoreactivity) were measured during day 2 insulin-induced hypoglycemia (0.5 U insulin · 100 g body wt−1· h−1iv for 2 h) after day 1 hypoglycemia (Hypo-Hypo) or vehicle. Hypo-Hypo animals demonstrated HAAF with blunted epinephrine, glucagon, and corticosterone (Cort) responses and decreased activation of the medial hypothalamus [the paraventricular (PVN), dorsomedial (DMH), and arcuate (Arc) nuclei]. To evaluate whether increases in day 1 Cort were responsible for the decreased hypothalamic activation, Cort was infused intracerebroventricularly (72 μg) on day 1 and the response to day 2 hypoglycemia was measured. Intracerebroventricular Cort infusion failed to alter the neuroendocrine response to day 2 hypoglycemia, despite elevating both central nervous system and peripheral Cort levels. However, day 1 Cort blunted responses in two of the same hypothalamic regions as Hypo-Hypo (the DMH and Arc) but not in the PVN. These results suggest that decreased activation of the PVN may be important in the development of HAAF and that antecedent exposure to elevated levels of Cort is not always sufficient to produce HAAF.

scholarly journals AMPA receptors and stargazin-like transmembrane AMPA receptor-regulatory proteins mediate hippocampal kainate neurotoxicity

2007 ◽  
Vol 104 (47) ◽  
pp. 18784-18788 ◽  
Author(s):  
S. Tomita ◽  
R. K. Byrd ◽  
N. Rouach ◽  
C. Bellone ◽  
A. Venegas ◽  
...  
Keyword(s):  
Ampa Receptor ◽  
Ampa Receptors ◽  
Regulatory Proteins

scholarly journals Inhibition of Brain Prostaglandin Endoperoxide Synthase-2 Prevents the Preparturient Increase in Fetal Adrenocorticotropin Secretion in the Sheep Fetus

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 4128-4136 ◽  
Author(s):  
Jason Gersting ◽  
Christine E. Schaub ◽  
Maureen Keller-Wood ◽  
Charles E. Wood
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Fetal Brain ◽  
Brain Regions ◽  
Acth Secretion ◽  
Fetal Sheep ◽  
Prostaglandin Endoperoxide ◽  
Fetal Plasma ◽  
Prostaglandin Endoperoxide Synthase

Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth. Recently, we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal ACTH secretion. The present study was designed to test the hypothesis that the preparturient increase in fetal ACTH secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase (PGHS)-2 (cyclooxygenase-2) in the fetal brain. We performed two studies in chronically catheterized fetal sheep. In the first study, we infused nimesulide or vehicle intracerebroventricularly (icv) into singleton fetal sheep and collected blood samples until spontaneous parturition. Nimesulide significantly delayed parturition, and inhibited fetal ACTH and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration. In the second study, we used twin fetuses. One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle. Nimesulide reduced brain tissue concentrations of prostaglandin estradiol, while not affecting plasma prostaglandin E2 concentrations, demonstrating an action restricted to the fetal brain. Nimesulide reduced PGHS-2 mRNA and increased PGHS-2 protein, while not altering PGHS-1 mRNA or protein in most brain regions, suggesting an effect of the inhibitor on PGHS-2 turnover and relative specificity for PGHS-2 in vivo. We conclude that the preparturient increase in fetal ACTH and proopiomelanocortin is dependent upon the activity of PGHS-2 in the fetal brain. However, we also conclude that the timing of parturition is not solely dependent upon ACTH in this species.

scholarly journals Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

2014 ◽  
Vol 306 (7) ◽  
pp. R457-R469 ◽  
Author(s):  
Amit D. Gujar ◽  
Baher A. Ibrahim ◽  
Pratistha Tamrakar ◽  
Ajeesh Koshy Cherian ◽  
Karen P. Briski
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Fourth Ventricle ◽  
Brain Regions ◽  
Monocarboxylate Transporter ◽  
Catecholaminergic Neurons ◽  
Lateral Hypothalamic ◽  
Metabolic Monitoring ◽  
Ampk Activity ◽  
6 Hydroxydopamine

Nerve cell metabolic activity is monitored in multiple brain regions, including the hypothalamus and hindbrain dorsal vagal complex (DVC), but it is unclear if individual metabolosensory loci operate autonomously or interact to coordinate central nervous system (CNS) reactivity to energy imbalance. This research addressed the hypothesis that hypoglycemia-associated DVC lactoprivation stimulates hypothalamic AMPK activity and metabolic neurotransmitter expression. As DVC catecholaminergic neurons express biomarkers for metabolic monitoring, we investigated whether these cells are a source of lactate deficit signaling to the hypothalamus. Caudal fourth ventricle (CV4) infusion of the glucose metabolite l-lactate during insulin-induced hypoglycemia reversed changes in DVC A2 noradrenergic, arcuate neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), and lateral hypothalamic orexin-A (ORX) neuronal AMPK activity, coincident with exacerbation of hypoglycemia. Hindbrain lactate repletion also blunted hypoglycemic upregulation of arcuate NPY mRNA and protein. This treatment did not alter hypoglycemic paraventricular oxytocin (OT) and lateral hypothalamic ORX mRNA profiles, but exacerbated or reversed adjustments in OT and ORX neuropeptide synthesis, respectively. CV4 delivery of the monocarboxylate transporter inhibitor, 4-CIN, increased A2 phosphoAMPK (pAMPK), elevated circulating glucose, and stimulated feeding, responses that were attenuated by 6-hydroxydopamine pretreatment. 4-CIN-infused rats exhibited increased (NPY, ORX neurons) or decreased (POMC neurons) pAMPK concurrent with hyperglycemia. These data show that hindbrain lactoprivic signaling regulates hypothalamic AMPK and key effector neurotransmitter responses to hypoglycemia. Evidence that A2 AMPK activity is lactate-dependent, and that DVC catecholamine cells are critical for lactoprivic control of glucose, feeding, and hypothalamic AMPK, implies A2 derivation of this metabolic regulatory stimulus.

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