Biomedical subjects

J M Henley

Publications and source records attributed to J M Henley.

At least 37 records · Page 2Linked to original sources

PubMed1999

Kainate receptors: subunits, synaptic localization and function.

Although it is well established that kainate receptors constitute an entirely separate group of proteins from AMPA receptors, their physiological functions remain unclear. The molecular cloning of subunits that form kainate receptors and the ability to study recombinant receptors is leading to an increased understanding of their functional properties. Furthermore, the development of kainate receptor-selective agonists and antagonists over the past few years is now allowing the physiological roles of these receptors and, in some cases, specific subunits to be investigated. As a consequence, the synaptic activation of postsynaptic kainate receptors and the presence of presynaptic kainate receptors that serve to regulate excitatory and inhibitory synaptic transmission have been described, and will be discussed in this article by Ramesh Chittajallu, Steven Braithwaite, Vernon Clarke and Jeremy Henley.

Animals↗

PubMed1999

Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism.

Here, we show that disruption of N-ethylmaleimide-sensitive fusion protein- (NSF-) GluR2 interaction by infusion into cultured hippocampal neurons of a blocking peptide (pep2m) caused a rapid decrease in the frequency but no change in the amplitude of AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs). N-methyl-D-aspartate (NMDA) receptor-mediated mEPSCs were not changed. Viral expression of pep2m reduced the surface expression of alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA) receptors, whereas NMDA receptor surface expression in the same living cells was unchanged. In permeabilized neurons, the total amount of GluR2 immunoreactivity was unchanged, and a punctate distribution of GluR2 was observed throughout the dendritic tree. These data suggest that the NSF-GluR2 interaction is required for the surface expression of GluR2-containing AMPA receptors and that disruption of the interaction leads to the functional elimination of AMPA receptors at synapses.

Adenoviridae↗

PubMed1999

Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF-GluR2 interaction.

We investigated whether the interaction between the N-ethyl-maleimide-sensitive fusion protein (NSF) and the AMPA receptor (AMPAR) subunit GluR2 is involved in synaptic plasticity in the CA1 region of the hippocampus. Blockade of the NSF-GluR2 interaction by a specific peptide (pep2m) introduced into neurons prevented homosynaptic, de novo long-term depression (LTD). Moreover, saturation of LTD prevented the pep2m-induced reduction in AMPAR-mediated excitatory postsynaptic currents (EPSCs). Minimal stimulation experiments indicated that both pep2m action and LTD were due to changes in quantal size and quantal content but were not associated with changes in AMPAR single-channel conductance or EPSC kinetics. These results suggest that there is a pool of AMPARs dependent on the NSF-GluR2 interaction and that LTD expression involves the removal of these receptors from synapses.

Animals↗

PubMed1998

Different effects of phospholipase A2 on agonist binding to hippocampal, cortical and recombinant homomeric alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors.

Secretory phospholipase A2 (sPLA2) has been reported to modulate agonist and antagonist binding to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Here we report that in hippocampal membranes sPLA2 increases the affinity of [3H]AMPA binding whereas in cortical membranes the affinity of binding is decreased. To test whether these results are due to the interaction of sPLA2 with different AMPA receptor subunits we used membranes from BHK cells expressing homomeric GluR1, GluR2 or GluR4 receptors. Pretreatment with the enzyme had no effect on [3H]AMPA binding to any of the homomeric receptors. We interpret these data to suggest that sPLA2 does not act directly at the AMPA receptor. Instead, sPLA2 may interact with a receptor-associated protein present in brain but not in BHK cells and this interaction may exert different effects in cortex and hippocampus.

Animals↗

PubMed1998

The regulation of AMPA receptor-binding sites.

A wide variety of mechanisms have been identified that can regulate the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor complex. Modulation has been shown to occur at the nucleic acid level via RNA editing and alternative splicing. At the posttranslational level, processes such as phosphorylation, glycosylation, chemical modification of reactive groups on the receptor proteins, interaction with a putative receptor-associated modulatory protein, and changes in the lipid environment have been reported to regulate receptor binding and function. In this review, we discuss general aspects of the cell biology, pharmacology, and function of AMPA receptors. In particular, we focus on some factors shown to modulate agonist binding and discuss possible molecular mechanisms underlying the regulation observed.

Alternative Splicing↗

PubMed1998

NSF binding to GluR2 regulates synaptic transmission.

Here, we show that N-ethylmaleimide-sensitive fusion protein (NSF) interacts directly and selectively with the intracellular C-terminal domain of the GluR2 subunit of AMPA receptors. The interaction requires all three domains of NSF but occurs between residues Lys-844 and Gln-853 of rat GluR2, with Asn-851 playing a critical role. Loading of decapeptides corresponding to the NSF-binding domain of GluR2 into rat hippocampal CA1 pyramidal neurons results in a marked, progressive decrement of AMPA receptor-mediated synaptic transmission. This reduction in synaptic transmission was also observed when an anti-NSF monoclonal antibody (mAb) was loaded into CA1 neurons. These results demonstrate a previously unsuspected direct interaction in the postsynaptic neuron between two major proteins involved in synaptic transmission and suggest a rapid NSF-dependent modulation of AMPA receptor function.

Amino Acid Sequence↗

PubMed1997

High-affinity binding sites for 125I-labelled pancreatic secretory phospholipase A2 in rat brain.

Porcine pancreatic secretory phospholipase A2 (ppsPLA2) has been shown to modulate agonist and antagonist binding to alpha-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA) receptors and to effect neurotransmission in the central nervous system (CNS). To further elucidate the mechanism of action of ppsPLA2 in the CNS, the binding profile of 125I-labelled ppsPLA2 to rat whole-brain membranes was assessed. Two classes of calcium-dependent binding sites were detected using unlabelled ppsPLA2 as a displacer with IC50 values of 3 and 217 nM. Similar values were obtained for [125I]ppsPLA2 binding to membranes prepared from isolated cortical and hippocampal rat brain regions. [125I]ppsPLA2 binding displayed bell-shaped concentration-dependence curves to Ca2+, Zn2 + and pH. Binding was not inhibited by AMPA, the false substrate, oleoyloxyethyl phosphocholine (OOPC), or by BSA-galactose or wheat germ agglutinin. [125I]ppsPLA2 binding was reduced by treatment of the rat brain membranes with mercaptoethanol and proteinase K treatment or by their pre-incubation at 95 degrees C. These results show a different binding profile to the previously characterised snake venom sPLA2 N-type receptors and suggest the existence of novel class of sPLA2 N-type binding sites.

Animals↗

PubMed1997

(RS)-2-chloro-5-hydroxyphenylglycine (CHPG) activates mGlu5, but no mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus.

A new phenylglycine derivative, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), has been synthesized and shown to selectively activate mGlu5a receptors, compared to mGlu1 alpha receptors, when expressed in CHO cells. This selective mGlu5 receptor agonist also potentiates NMDA-induced depolarizations in rat hippocampal slices. CHPG may be a useful tool for studying the role of mGlu5 receptors in the central nervous system.

Animals↗

PubMed1997