Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia

2018 ◽  
Vol 129 (3) ◽  
pp. 477-489 ◽  
Author(s):  
Dian-Shi Wang ◽  
Kirusanthy Kaneshwaran ◽  
Gang Lei ◽  
Fariya Mostafa ◽  
Junhui Wang ◽  
...  
Keyword(s):  
Problem Solving ◽  
Adrenergic Receptor ◽  
Hippocampal Neurons ◽  
Type A ◽  
Surface Expression ◽  
Aminobutyric Acid ◽  
Cell Surface Expression ◽  
Receptor Function ◽  
Anesthetic Drugs ◽  
Acid Type

Abstract What We Already Know about This Topic What This Article Tells Us That Is New Background Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. Methods Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. Results The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. Conclusions Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.

scholarly journals Assembly and Cell Surface Expression of Heteromeric and Homomeric -Aminobutyric Acid Type A Receptors

1996 ◽  
Vol 271 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Christopher N. Connolly ◽  
Belinda J. Krishek ◽  
Bernard J. McDonald ◽  
Trevor G. Smart ◽  
Stephen J. Moss
Keyword(s):  
Cell Surface ◽  
Type A ◽  
Surface Expression ◽  
Aminobutyric Acid ◽  
Cell Surface Expression ◽  
Acid Type

scholarly journals Phospholipase C-related but Catalytically Inactive Protein Is Required for Insulin-induced Cell Surface Expression of γ-Aminobutyric Acid Type A Receptors

2009 ◽  
Vol 285 (7) ◽  
pp. 4837-4846 ◽  
Author(s):  
Makoto Fujii ◽  
Takashi Kanematsu ◽  
Hitoshi Ishibashi ◽  
Kiyoko Fukami ◽  
Tadaomi Takenawa ◽  
...  
Keyword(s):  
Cell Surface ◽  
Phospholipase C ◽  
Type A ◽  
Surface Expression ◽  
Aminobutyric Acid ◽  
Cell Surface Expression ◽  
Acid Type ◽  
Inactive Protein

scholarly journals Bilateral Inhibition of γ-Aminobutyric Acid Type A Receptor Function within the Basolateral Amygdala Blocked Propofol-induced Amnesia and Activity-regulated Cytoskeletal Protein Expression Inhibition in the Hippocampus

2008 ◽  
Vol 109 (5) ◽  
pp. 775-781 ◽  
Author(s):  
Yu Ren ◽  
Fu-Jun Zhang ◽  
Qing-Sheng Xue ◽  
Xin Zhao ◽  
Bu-Wei Yu
Keyword(s):  
Protein Expression ◽  
Basolateral Amygdala ◽  
Mrna Level ◽  
Type A ◽  
Memory Formation ◽  
Aminobutyric Acid ◽  
Receptor Function ◽  
Amnesic Effect ◽  
Bicuculline Methiodide ◽  
Acid Type

Background It has been reported that bilateral lesions of the basolateral amygdala complex (BLA) blocked propofol-induced amnesia of inhibitory avoidance (IA) training. Based on these results, the authors hypothesized that the amnesia effect of propofol was partly due to its impairment of memory formation in the hippocampus through activating the BLA gamma-aminobutyric acid type A receptor function. The authors determined the changes in activity-regulated cytoskeleton-associated protein (Arc) expression to be an indicator of IA memory formation. Methods Male Sprague-Dawley rats received bilateral injection of bicuculline methiodide (10, 50, or 100 pmol/0.5 microl) or saline (0.5 microl) into the BLA. Fifteen minutes later, the rats were intraperitoneally injected with either propofol (25 mg/kg) or saline. After 5 min, the one-trial IA training was conducted. Rats intraperitoneally infused with saline served as controls and only received saline injections into the BLA. Twenty-four hours later, the IA retention latency was tested. Separate groups of rats treated the same way were killed either 30 min after IA training for hippocampal Arc mRNA measurement or after 45 min for protein level quantification. Results The largest dose of bicuculline methiodide (100 pmol) not only blocked the propofol-induced amnesia but also reversed the inhibition effect of propofol on Arc protein expression in the hippocampus (P < 0.05). However, the mRNA level of Arc showed no significant changes after propofol and bicuculline methiodide administration. Conclusions The amnesic effect of propofol seems to involve the modulation of Arc protein expression in the hippocampus, occurring through a network interaction with the BLA.

RNA editing and its impact on GABAA receptor function

2009 ◽  
Vol 37 (6) ◽  
pp. 1399-1403 ◽  
Author(s):  
Chammiran Daniel ◽  
Marie Öhman
Keyword(s):  
Rna Editing ◽  
Surface Expression ◽  
Aminobutyric Acid ◽  
Brain Maturation ◽  
Cell Surface Expression ◽  
Receptor Subtypes ◽  
Protein Diversity ◽  
Adenosine Deaminases ◽  
Acid Type ◽  
The Impact

A-to-I (adenosine-to-inosine) RNA editing catalysed by the ADARs (adenosine deaminases that act on RNA) is a post-transcriptional event that contributes to protein diversity in metazoans. In mammalian neuronal ion channels, editing alters functionally important amino acids and creates receptor subtypes important for the development of the nervous system. The excitatory AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate glutamate receptors, as well as the inhibitory GABAA [GABA (γ-aminobutyric acid) type A] receptor, are subject to A-to-I RNA editing. Editing affects several features of the receptors, including kinetics, subunit assembly and cell-surface expression. Here, we discuss the regulation of editing during brain maturation and the impact of RNA editing on the expression of different receptor subtypes.

The Plasticizer Di(2-ethylhexyl) Phthalate Modulates ??-Aminobutyric Acid Type A and Glycine Receptor Function

2007 ◽  
Vol 105 (2) ◽  
pp. 393-396 ◽  
Author(s):  
Liya Yang ◽  
Pavle S. Milutinovic ◽  
Robert J. Brosnan ◽  
Edmond I Eger ◽  
James M. Sonner
Keyword(s):  
Glycine Receptor ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Function ◽  
Acid Type ◽  
Ethylhexyl Phthalate

Droperidol Inhibits GABAAand Neuronal Nicotinic Receptor Activation

2002 ◽  
Vol 96 (4) ◽  
pp. 987-993 ◽  
Author(s):  
Pamela Flood ◽  
Kristen M. Coates
Keyword(s):  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Hill Coefficient ◽  
High Dose ◽  
Gamma Aminobutyric Acid ◽  
Anesthetic Drugs ◽  
Gaba Inhibition ◽  
Acid Type ◽  
Anesthetic Action

Background Droperidol is used in neuroleptanesthesia and as an antiemetic. Although its antiemetic effect is thought to be caused by dopaminergic inhibition, the mechanism of droperidol's anesthetic action is unknown. Because gamma-aminobutyric acid type A (GABAA) and neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as putative targets of other general anesthetic drugs, the authors tested the ability of droperidol to modulate these receptors. Methods gamma-Aminobutyric acid type A alpha1beta1gamma2 receptor, alpha7 and alpha4beta2 nAChRs were expressed in Xenopus oocytes and studied with two-electrode voltage clamp recording. The authors tested the ability of droperidol at concentrations from 1 nm to 100 microm to modulate activation of these receptors by their native agonists. Results Droperidol inhibited the GABA response by a maximum of 24.7 +/- 3.0%. The IC50 for inhibition was 12.6 +/- 0.47 nm droperidol. At high concentrations, droperidol (100 microm) activates the GABAA receptor in the absence of GABA. Inhibition of the GABA response is significantly greater at hyperpolarized membrane potentials. The activation of the alpha7 nAChR is also inhibited by droperidol, with an IC50 of 5.8 +/- 0.53 microm. The Hill coefficient is 0.95 +/- 0.1. Inhibition is noncompetitive, and membrane voltage dependence is insignificant. Conclusions Droperidol inhibits activation of both the GABAA alpha1beta1gamma2 and alpha7 nAChR. The submaximal GABA inhibition occurs within a concentration range such that it might be responsible for the anxiety, dysphoria, and restlessness that limit the clinical utility of high-dose droperidol anesthesia. Inhibition of the alpha7 nAChR might be responsible for the anesthetic action of droperidol.

scholarly journals A Conserved Tyrosine in the β2Subunit M4 Segment Is a Determinant of γ-Aminobutyric Acid Type A Receptor Sensitivity to Propofol

2007 ◽  
Vol 107 (3) ◽  
pp. 412-418 ◽  
Author(s):  
James E. Richardson ◽  
Paul S. Garcia ◽  
Kate K. O'Toole ◽  
Jason M. C. Derry ◽  
Shannon V. Bell ◽  
...  
Keyword(s):  
Binding Site ◽  
Type A ◽  
Receptor Activation ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetics ◽  
Receptor Function ◽  
293 Cells ◽  
Acid Type ◽  
Normal Sensitivity

Background The gamma-aminobutyric acid type A receptor (GABAA-R) beta subunits are critical targets for the actions for several intravenous general anesthetics, but the precise nature of the anesthetic binding sites are unknown. In addition, little is known about the role the fourth transmembrane (M4) segment of the receptor plays in receptor function. The aim of this study was to better define the propofol binding site on the GABAA-R by conducting a tryptophan scan in the M4 segment of the beta2 subunit. Methods Seven tryptophan mutations were introduced into the C-terminal end of the M4 segment of the GABAA-R beta2 subunit. GABAA-R subunit complementary DNAs were transfected into human embryonic kidney 293 cells grown on glass coverslips. After transfection (36-72 h), coverslips were transferred to a perfusion chamber to assay receptor function. Cells were whole cell patch clamped and exposed to GABA, propofol, etomidate, and pregnenolone. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger. Results All tryptophan mutations were well tolerated, and with one exception, all resulted in minimal changes in receptor activation by GABA. One mutation, beta2(Y444W), selectively suppressed the ability of propofol to enhance receptor function while retaining normal sensitivity to etomidate and pregnenolone. Conclusions This is the first report of a mutation that selectively reduces propofol sensitivity without altering the action of etomidate. The reduction in propofol sensitivity is consistent with the loss of a hydrogen bond within the propofol binding site. These results also suggest a possible orientation of the propofol molecule within its binding site.

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