Sedation and anesthesia mediated by distinct GABAA receptor isoforms

David S. Reynolds; Thomas W. Rosahl; Jennifer Cirone; Gillian F. O'Meara; Alison Haythornthwaite; Richard J. Newman; Janice Myers; Cyrille Sur; Owain Howell; A. Richard Rutter; John Atack; Alison J. Macaulay; Karen L. Hadingham; Peter H. Hutson; Delia Belelli; Jeremy Lambert; Gerard R. Dawson; Ruth McKernan; Paul J. Whiting; Keith A. Wafford

Sedation and anesthesia mediated by distinct GABAA receptor isoforms

David S. Reynolds
, Thomas W. Rosahl
, Jennifer Cirone
, Gillian F. O'Meara
, Alison Haythornthwaite
, Richard J. Newman
, Janice Myers
, Cyrille Sur
, Owain Howell
, A. Richard Rutter
, John Atack
, Alison J. Macaulay
, Karen L. Hadingham
, Peter H. Hutson
, Delia Belelli
, Jeremy Lambert
, Gerard R. Dawson
, Ruth McKernan
, Paul J. Whiting
, Keith A. Wafford

Research output: Contribution to journal › Article › peer-review

Abstract

The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABAA receptors, with selectivity for 2 and 3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive 2 subunit (2 N265S) to determine the role of 2 and 3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through 3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the 2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABAA receptor subtypes.

Original language	English
Pages (from-to)	8608-8617
Number of pages	10
Journal	Journal of Neuroscience
Volume	23
Issue number	24
Publication status	Published - Sept 2003

Keywords

Anaesthetics pharmacology
Etomidate pharmacology
Hypnotics and sedatives pharmacology
Receptors
GABA-A metabolism

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http://www.jneurosci.org/content/23/24.toc

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Reynolds, D. S., Rosahl, T. W., Cirone, J., O'Meara, G. F., Haythornthwaite, A., Newman, R. J., Myers, J., Sur, C., Howell, O., Rutter, A. R., Atack, J., Macaulay, A. J., Hadingham, K. L., Hutson, P. H., Belelli, D., Lambert, J., Dawson, G. R., McKernan, R., Whiting, P. J., & Wafford, K. A. (2003). Sedation and anesthesia mediated by distinct GABAA receptor isoforms. Journal of Neuroscience, 23(24), 8608-8617. http://www.jneurosci.org/content/23/24.toc

@article{d1a6a7fa1ada4102b401d06c0dda8cba,

title = "Sedation and anesthesia mediated by distinct GABAA receptor isoforms",

abstract = "The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABAA receptors, with selectivity for 2 and 3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive 2 subunit (2 N265S) to determine the role of 2 and 3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through 3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the 2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABAA receptor subtypes.",

keywords = "Anaesthetics pharmacology, Etomidate pharmacology, Hypnotics and sedatives pharmacology, Receptors, GABA-A metabolism",

author = "Reynolds, \{David S.\} and Rosahl, \{Thomas W.\} and Jennifer Cirone and O'Meara, \{Gillian F.\} and Alison Haythornthwaite and Newman, \{Richard J.\} and Janice Myers and Cyrille Sur and Owain Howell and Rutter, \{A. Richard\} and John Atack and Macaulay, \{Alison J.\} and Hadingham, \{Karen L.\} and Hutson, \{Peter H.\} and Delia Belelli and Jeremy Lambert and Dawson, \{Gerard R.\} and Ruth McKernan and Whiting, \{Paul J.\} and Wafford, \{Keith A.\}",

note = "dc.publisher: Society for Neuroscience dc.description.sponsorship: A.H. is supported by a Biotechnology and Biological Sciences Research Council-funded CASE award with Merck Sharp \& Dohme ",

year = "2003",

month = sep,

language = "English",

volume = "23",

pages = "8608--8617",

journal = "Journal of Neuroscience",

issn = "0270-6474",

publisher = "Society for Neuroscience",

number = "24",

}

Reynolds, DS, Rosahl, TW, Cirone, J, O'Meara, GF, Haythornthwaite, A, Newman, RJ, Myers, J, Sur, C, Howell, O, Rutter, AR, Atack, J, Macaulay, AJ, Hadingham, KL, Hutson, PH, Belelli, D, Lambert, J, Dawson, GR, McKernan, R, Whiting, PJ & Wafford, KA 2003, 'Sedation and anesthesia mediated by distinct GABAA receptor isoforms', Journal of Neuroscience, vol. 23, no. 24, pp. 8608-8617. <http://www.jneurosci.org/content/23/24.toc>

TY - JOUR

T1 - Sedation and anesthesia mediated by distinct GABAA receptor isoforms

AU - Reynolds, David S.

AU - Rosahl, Thomas W.

AU - Cirone, Jennifer

AU - O'Meara, Gillian F.

AU - Haythornthwaite, Alison

AU - Newman, Richard J.

AU - Myers, Janice

AU - Sur, Cyrille

AU - Howell, Owain

AU - Rutter, A. Richard

AU - Atack, John

AU - Macaulay, Alison J.

AU - Hadingham, Karen L.

AU - Hutson, Peter H.

AU - Belelli, Delia

AU - Lambert, Jeremy

AU - Dawson, Gerard R.

AU - McKernan, Ruth

AU - Whiting, Paul J.

AU - Wafford, Keith A.

N1 - dc.publisher: Society for Neuroscience dc.description.sponsorship: A.H. is supported by a Biotechnology and Biological Sciences Research Council-funded CASE award with Merck Sharp & Dohme

PY - 2003/9

Y1 - 2003/9

N2 - The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABAA receptors, with selectivity for 2 and 3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive 2 subunit (2 N265S) to determine the role of 2 and 3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through 3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the 2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABAA receptor subtypes.

AB - The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABAA receptors, with selectivity for 2 and 3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive 2 subunit (2 N265S) to determine the role of 2 and 3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through 3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the 2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABAA receptor subtypes.

KW - Anaesthetics pharmacology

KW - Etomidate pharmacology

KW - Hypnotics and sedatives pharmacology

KW - Receptors

KW - GABA-A metabolism

M3 - Article

SN - 0270-6474

VL - 23

SP - 8608

EP - 8617

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 24

ER -

Sedation and anesthesia mediated by distinct GABAA receptor isoforms

Abstract

Keywords

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