Vesicular uptake of N-acetylaspartylglutamate is catalysed by sialin (SLC17A5)

2013 ◽  
Vol 454 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Julia Lodder-Gadaczek ◽  
Volkmar Gieselmann ◽  
Matthias Eckhardt
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Dependent Manner ◽  
Type Ii ◽  
Metabotropic Glutamate ◽  
Calcium Dependent ◽  
Vesicular Transporter ◽  
Vesicular Uptake ◽  
A Cell ◽  
Dependent Transport ◽  
Deficient Mice

NAAG (N-acetylaspartylglutamate) is an abundant neuropeptide in the vertebrate nervous system. It is released from synaptic terminals in a calcium-dependent manner and has been shown to act as an agonist at the type II metabotropic glutamate receptor mGluR3. It has been proposed that NAAG may also be released from axons. So far, however, it has remained unclear how NAAG is transported into synaptic or other vesicles before it is secreted. In the present study, we demonstrate that uptake of NAAG and the related peptide NAAG2 (N-acetylaspartylglutamylglutamate) into vesicles depends on the sialic acid transporter sialin (SLC17A5). This was demonstrated using cell lines expressing a cell surface variant of sialin and by functional reconstitution of sialin in liposomes. NAAG uptake into sialin-containing proteoliposomes was detectable in the presence of an active H+-ATPase or valinomycin, indicating that transport is driven by membrane potential rather than H+ gradient. We also show that sialin is most probably the major and possibly only vesicular transporter for NAAG and NAAG2, because ATP-dependent transport of both peptides was not detectable in vesicles isolated from sialin-deficient mice.

Metabotropic glutamate receptor agonist-induced hyperpolarizations in rat basolateral amygdala neurons: receptor characterization and ion channels

1996 ◽  
Vol 76 (5) ◽  
pp. 3059-3069 ◽  
Author(s):  
K. H. Holmes ◽  
N. B. Keele ◽  
V. L. Arvanov ◽  
P. Shinnick-Gallagher
Keyword(s):  
Dicarboxylic Acid ◽  
Glutamate Receptor ◽  
Basolateral Amygdala ◽  
Metabotropic Glutamate Receptor ◽  
Outward Current ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Metabotropic Glutamate ◽  
Outward Currents

1. Metabotropic glutamate receptor (mGluR)-agonist-induced hyperpolarizations and corresponding outward currents were analyzed in basolateral amygdala (BLA) neurons in rat brain slice preparations with current-clamp and single-electrode voltage-clamp recording to characterize the mGluR subtype(s) and the ion channel(s) mediating this response. 2. The mGluR agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) induced a membrane hyperpolarization or outward current in BLA neurons in a concentration-dependent manner (median effective concentration = 34 microM; range = 10-200 microM); the 1S,3R-ACPD hyperpolarizations are recorded in 89% of neurons that accommodate or cease firing in response to a 400-ms depolarizing current injection (0.5 nA). 3. mGluR agonists elicited hyperpolarizations or outward currents in a concentration-dependent manner in the following rank order of potency: (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I) > 1S,3R-ACPD > (s)-4-carboxyphenylglycine = (RS)-4-carboxy-3-hydroxyphenylglycine (4C3HPG) > L-aminophosphonobutyric acid > (1S,3S)-1-amino-cyclopentane-1,3-dicarboxylic acid. In contrast, the mGluR agonists quisqualate and ibotenate induced only depolarizations in the presence of D-2-amino-5-phosphonovalerate and 6-cyano-7-nitroquinoxaline-2,3-dione in BLA neurons. 4. The 1S,3R-ACPD-induced outward current is mediated through a large-conductance calcium-dependent potassium (BK) conductance. The BK channel blockers iberiotoxin and charybdotoxin blocked the response, as did the potassium channel blockers tetraethylammonium and 4-aminopyridine; the small-conductance calcium-activated potassium channel blocker apamin did not affect the response. 5. The mGluR-agonist-induced hyperpolarization is blocked in amygdala slices from animals pretreated with pertussis toxin (PTX). 1S,3R-ACPD hyperpolarizations were recorded in neurons contralateral but not ipsilateral to the site of PTX injection. 6. The antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG, 500 microM) reduced significantly the 1S,3R-ACPD-induced hyperpolarization. 7. In conclusion, the relative potency of L-CCG-I and 4C3HPG in evoking only hyperpolarizations (outward currents) in accommodating neurons, and the observation that MCPG (500 microM) reduces the hyperpolarization, suggest that a group-II-like mGluR underlies the hyperpolarizing response. The mGluR-induced response is sensitive to iberiotoxin and to pretreatment with PTX, suggesting activation of BK channels through a group II mGluR linked to a PTX-sensitive G protein in BLA neurons.

scholarly journals Two Distinct Notch1 Mutant Alleles Are Involved in the Induction of T-Cell Leukemia in c-myc Transgenic Mice

2000 ◽  
Vol 20 (11) ◽  
pp. 3831-3842 ◽  
Author(s):  
C. D. Hoemann ◽  
N. Beaulieu ◽  
L. Girard ◽  
N. Rebai ◽  
P. Jolicoeur
Keyword(s):  
Cell Surface ◽  
Transgenic Mice ◽  
Intracellular Signaling ◽  
Transmembrane Domain ◽  
Tumor Formation ◽  
Type I ◽  
Dependent Manner ◽  
Type Ii ◽  
Extracellular Medium ◽  
Calcium Dependent

ABSTRACT We have previously characterized a large panel of provirus insertion Notch1 mutant alleles and their products arising in thymomas of MMTVD/myc transgenic mice. Here, we show that these Notch1 mutations represent two clearly distinct classes. In the first class (type I), proviral integrations were clustered just upstream of sequences encoding the transmembrane domain. Type I Notch1 alleles produced two types of mutantNotch1 RNA, one of which encoded the entire Notch1 cytoplasmic domain [N(IC)] and the other of which encoded a soluble ectodomain [N(EC)Mut] which, in contrast to the processed wild-type ectodomain [N(EC)WT], did not reside at the cell surface and became secreted in a temperature-dependent manner. A second, novel class of mutant Notch1 allele (type II) encoded a Notch1 receptor with the C-terminal PEST motif deleted (ΔCT). The type II Notch1ΔCT protein was expressed as a normally processed receptor [N(EC)WT and N(IC)ΔCT] at the cell surface, and its ectodomain was found to be shed into the extracellular medium in a temperature- and calcium-dependent manner. These data suggest that both type I and type II mutations generate two structurally distinct Notch1 N(EC) and N(IC) proteins that may participate in tumor formation, in collaboration with the c-myc oncogene, through distinct mechanisms. Constitutive type I N(IC) and type II N(IC)ΔCT expression may enhance Notch1 intracellular signaling, while secreted or shed type I N(EC)Mut and type II N(EC) proteins may differentially interact in an autocrine or paracrine fashion with ligands of Notch1 and affect their signaling.

Impaired behavioral suppression by light in metabotropic glutamate receptor subtype 6-deficient mice

Neuroscience ◽  
2000 ◽  
Vol 97 (4) ◽  
pp. 779-787 ◽  
Author(s):  
M Takao ◽  
K Morigiwa ◽  
H Sasaki ◽  
T Miyoshi ◽  
T Shima ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Behavioral Suppression ◽  
Deficient Mice

Role of metabotropic glutamate receptors in vasopressin and oxytocin release

2001 ◽  
Vol 281 (2) ◽  
pp. R452-R458 ◽  
Author(s):  
Delmore J. Morsette ◽  
Hanna Sidorowicz ◽  
Celia D. Sladek
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Dependent Manner ◽  
Hormone Release ◽  
Concentration Dependent Manner ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Oxytocin Release

The effect of metabotropic glutamate receptor (mGluR) activation on vasopressin (VP) and oxytocin (OT) release was evaluated using explants of the hypothalamoneurohypophysial system. (+/−)-1-Aminocyclopentane- trans-1,3-dicarboxylic acid (t-ACPD), an agonist at groups I and II mGluRs, increased VP and OT release in a concentration-dependent manner. A role for group I mGluRs in VP and OT release was demonstrated by the ability of a group I-specific mGluR antagonist, 1-aminoindan-1,5-idicarboxylic acid (AIDA), to block the effect of t-ACPD and the ability of a group I-specific agonist, ( R, S)-3,5-dihydroxyphenylglycine, to significantly increase both VP ( P = 0.0029) and OT ( P = 0.0032) release. However, AIDA did not alter VP or OT release induced by a ramp increase in osmolality of the perifusion medium. The role of group III mGluRs was examined using L(+)-2-amino-4-phosphonobutyric acid (L-AP4), an agonist of these receptors. L-AP4 did not change basal release of VP or OT and did not prevent osmotically stimulated hormone release. Thus mGluR activation stimulates VP and OT release, but it is not required for osmotic stimulation of hormone release.

scholarly journals Dissociation of impulsive traits by subthalamic metabotropic glutamate receptor 4

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Lukasz Piszczek ◽  
Andreea Constantinescu ◽  
Dominic Kargl ◽  
Jelena Lazovic ◽  
Anton Pekcec ◽  
...  
Keyword(s):  
Motor Control ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Hot Spot ◽  
Dependent Manner ◽  
Impulsive Behavior ◽  
Behavioral Strategies ◽  
Metabotropic Glutamate ◽  
Trait Impulsivity

Behavioral strategies require gating of premature responses to optimize outcomes. Several brain areas control impulsive actions, but the neuronal basis of natural variation in impulsivity between individuals remain largely unknown. Here, by combining a Go/No-Go behavioral assay with resting state (rs) functional MRI in mice, we identified the subthalamic nucleus (STN), a known gate for motor control in the basal ganglia, as a major hot spot for trait impulsivity. In vivo recorded STN neural activity encoded impulsive action as a separable state from basic motor control, characterized by decoupled STN/Substantia nigra pars reticulata (SNr) mesoscale networks. Optogenetic modulation of STN activity bi-directionally controlled impulsive behavior. Pharmacological and genetic manipulations showed that these impulsive actions are modulated by metabotropic glutamate receptor 4 (mGlu4) function in STN and its coupling to SNr in a behavioral trait-dependent manner, and independently of general motor function. In conclusion, STN circuitry multiplexes motor control and trait impulsivity, which are molecularly dissociated by mGlu4. This provides a potential mechanism for the genetic modulation of impulsive behavior, a clinically relevant predictor for developing psychiatric disorders associated with impulsivity.

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