Permeant Ion Effects on External Mg<sup>2+</sup>Block of NR1/2D NMDA Receptors

Qian, Anqi; Johnson, Jon W.

doi:10.1523/jneurosci.3453-06.2006

Cited by 29 publications

(34 citation statements)

References 61 publications

(90 reference statements)

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“…Extracellular [Mg 2+ ] was varied in a wide range from the full blockade to the total unblock of the NMDA receptors [34] (Figure 3A). We showed that in the control buffer ([Mg 2+ ] = 1,800 μM) there is no effect of GAT-2/3 blockade on the baseline current (Figures 2A and 3A).…”

Section: Resultsmentioning

confidence: 99%

Astrocytes convert network excitation to tonic inhibition of neurons

et al. 2012

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BackgroundGlutamate and γ-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters.ResultsHere we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na+ concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg2+] in vitro model of epilepsy. Under in vivo conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.ConclusionsThe results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamatergic excitation into GABAergic inhibition providing an adjustable, in situ negative feedback on the excitability of neurons.

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Section: Resultsmentioning

confidence: 99%

Astrocytes convert network excitation to tonic inhibition of neurons

et al. 2012

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“…In these examples, voltage-dependent block confers physiologically relevant strong voltage dependence on overall channel function. While block in these examples may be strongly sensitive to permeant ion concentrations due to knock off of block (35,43,50), it seems unlikely that changes in the concentration of permeant ions would be large enough to be a physiologically relevant regulator of channel activity via alterations in the degree of channel block. Alterations in the knock off of endogenous blocking molecules as a result of physiologically relevant changes in permeant ion concentrations, such as we propose here for CFTR, may therefore be a novel way in which ion channel function is regulated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CFTR chloride channel macroscopic conductance by extracellular bicarbonate

Holstead

Wang

et al. 2011

American Journal of Physiology-Cell Physiology

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Li MS, Holstead RG, Wang W, Linsdell P. Regulation of CFTR chloride channel macroscopic conductance by extracellular bicarbonate. Am J Physiol Cell Physiol 300: C65-C74, 2011. First published October 6, 2010 doi:10.1152/ajpcell.00290.2010.-The CFTR contributes to Cl Ϫ and HCO 3 Ϫ transport across epithelial cell apical membranes. The extracellular face of CFTR is exposed to varying concentrations of Cl Ϫ and HCO 3 Ϫ in epithelial tissues, and there is evidence that CFTR is sensitive to changes in extracellular anion concentrations. Here we present functional evidence that extracellular Cl Ϫ and HCO 3 Ϫ regulate anion conduction in open CFTR channels. Using cell-attached and inside-out patch-clamp recordings from constitutively active mutant E1371Q-CFTR channels, we show that voltage-dependent inhibition of CFTR currents in intact cells is significantly stronger when the extracellular solution contains HCO 3 Ϫ than when it contains Cl Ϫ . This difference appears to reflect differences in the ability of extracellular HCO 3 Ϫ and Cl Ϫ to interact with and repel intracellular blocking anions from the pore. Strong block by endogenous cytosolic anions leading to reduced CFTR channel currents in intact cells occurs at physiologically relevant HCO 3 Ϫ concentrations and membrane potentials and can result in up to ϳ50% inhibition of current amplitude. We propose that channel block by cytosolic anions is a previously unrecognized, physiologically relevant mechanism of channel regulation that confers on CFTR channels sensitivity to different anions in the extracellular fluid. We further suggest that this anion sensitivity represents a feedback mechanism by which CFTR-dependent anion secretion could be regulated by the composition of the secretions themselves. Implications for the mechanism and regulation of CFTR-dependent secretion in epithelial tissues are discussed. anion secretion; cystic fibrosis transmembrane conductance regulator; open channel block CYSTIC FIBROSIS (CF), a disease of deficient epithelial cell anion transport, is caused by genetic mutations that result in loss of function of the CFTR anion channel (15). CFTR is expressed in many different epithelial tissues, and, as a result, CF is associated with lung, pancreatic, gastrointestinal, and reproductive disease (45,46 (10,19,27). Again, the relative importance of direct HCO 3 Ϫ transport by CFTR vs.indirect, CFTR-regulated HCO 3 Ϫ transport by SLC26 proteins to overall epithelial cell HCO 3 Ϫ transport and their relevance to CF disease are the subject of current debate (24,29,51,55).Since CFTR is expressed in the apical membrane of epithelial cells, its extracellular face is exposed to epithelial secretions in the luminal fluid; the composition of this fluid may change dramatically under different conditions. The most striking example is the pancreatic duct, which in humans can secrete a fluid containing up to 140 mM HCO 3,5,7,13,25), and there is evidence that some epithelia may "switch" between Cl Ϫ and HCO 3 Ϫ secretion, depending on the stimulus (8,...

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“…Occupancy of these ion binding sites by Na ϩ or K ϩ alters the association and dissociation rates of Mg 2ϩ from its blocking site. The nature of these permeant ion-binding sites differs between GluN2 subunits (Qian and Johnson, 2006) and hence may underlie some GluN2-specific effects on Mg 2ϩ block Kuner and Schoepfer, 1996).…”

Section: Voltage-dependent Channel Block By Endogenous Ionsmentioning

confidence: 99%