Lack of alterations in muscarinic receptor subtypes and phosphoinositide hydrolysis upon acute DFP treatment

Catherine L. Cioffi; Esam E. El-Fakahany

doi:10.1016/0014-2999(88)90144-6

Lack of alterations in muscarinic receptor subtypes and phosphoinositide hydrolysis upon acute DFP treatment

Catherine L. Cioffi
, Esam E. El-Fakahany

Pharmacy Research and Graduate Education

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

9 Scopus citations

Abstract

There was a 25 and 27% reduction in the density of mouse brain muscarinic acetylcholine receptors 18 and 24 h following a single injection of the organophosphate diisopropylfluorophosphate (DFP) when the muscarinic antagonist [³H]N-methylscopolamine ([³H]NMS) was used as the ligand. Down-regulation of specific [³H]NMS binding was rapidly reversible reaching control levels 36 h after DFP administration. Carbamylcholine and pirenzepine competition for the specific binding of either [³H]NMS or [³H]quinuclidinyl benzilate ([³H]QNB) in brain homogenates from untreated and DFP-treated mice demonstrated that the alteration in muscarinic receptor density following acute DFP treatment was not accompanied by a change in a particular muscarinic receptor binding conformation. Furthermore, the magnitude of muscarinic receptor-mediated phosphoinositide hydrolysis was unchanged following short-term DFP treatment suggesting that a physiological desensitization in this response does not accompany acute down-regulation of [³H]NMS binding sites.

Original language	English (US)
Pages (from-to)	35-45
Number of pages	11
Journal	European Journal of Pharmacology
Volume	156
Issue number	1
DOIs	https://doi.org/10.1016/0014-2999(88)90144-6
State	Published - Oct 26 1988

Bibliographical note

Funding Information:
Muscarinic acetylcholine receptors mediate various types of biochemical responses such as inhibition of cyclic AMP synthesis, stimulation of cyclic GMP formation as well as phosphoinositide hydrolysis (McKinney and Richelson, 1984; Nathanson, 1987). Data from biochemical and physiological studies have provided insights into the heterogeneity of the muscarinic receptor. For i Supported in part by Grants NS-24158 and AG-07118 from the National Institutes of Health and by Contract DAAG-29-85-K-0123 from the U.S. Army Research Office. 2 Present address: Neuroscience Laboratory, University of Michigan, Ann Arbor, MI, U.S.A. Recipient of an Emerson Fellowship from the University of Maryland during the course of this work. * Recipient of a Research Career Development Award from the National Institutes of Health (AG-00344). To whom all correspondence should be addressed.

Keywords

(Down-regulation)
Di-isopropylfluorophosphate (DFP)
Muscarinic acetylcholine receptor subtypes
Organophosphate
Phosphoinositide metabolism
Pirenzepine
Tolerance

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title = "Lack of alterations in muscarinic receptor subtypes and phosphoinositide hydrolysis upon acute DFP treatment",

abstract = "There was a 25 and 27\% reduction in the density of mouse brain muscarinic acetylcholine receptors 18 and 24 h following a single injection of the organophosphate diisopropylfluorophosphate (DFP) when the muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) was used as the ligand. Down-regulation of specific [3H]NMS binding was rapidly reversible reaching control levels 36 h after DFP administration. Carbamylcholine and pirenzepine competition for the specific binding of either [3H]NMS or [3H]quinuclidinyl benzilate ([3H]QNB) in brain homogenates from untreated and DFP-treated mice demonstrated that the alteration in muscarinic receptor density following acute DFP treatment was not accompanied by a change in a particular muscarinic receptor binding conformation. Furthermore, the magnitude of muscarinic receptor-mediated phosphoinositide hydrolysis was unchanged following short-term DFP treatment suggesting that a physiological desensitization in this response does not accompany acute down-regulation of [3H]NMS binding sites.",

keywords = "(Down-regulation), Di-isopropylfluorophosphate (DFP), Muscarinic acetylcholine receptor subtypes, Organophosphate, Phosphoinositide metabolism, Pirenzepine, Tolerance",

author = "Cioffi, \{Catherine L.\} and El-Fakahany, \{Esam E.\}",

note = "Funding Information: Muscarinic acetylcholine receptors mediate various types of biochemical responses such as inhibition of cyclic AMP synthesis, stimulation of cyclic GMP formation as well as phosphoinositide hydrolysis (McKinney and Richelson, 1984; Nathanson, 1987). Data from biochemical and physiological studies have provided insights into the heterogeneity of the muscarinic receptor. For i Supported in part by Grants NS-24158 and AG-07118 from the National Institutes of Health and by Contract DAAG-29-85-K-0123 from the U.S. Army Research Office. 2 Present address: Neuroscience Laboratory, University of Michigan, Ann Arbor, MI, U.S.A. Recipient of an Emerson Fellowship from the University of Maryland during the course of this work. * Recipient of a Research Career Development Award from the National Institutes of Health (AG-00344). To whom all correspondence should be addressed.",

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T1 - Lack of alterations in muscarinic receptor subtypes and phosphoinositide hydrolysis upon acute DFP treatment

AU - Cioffi, Catherine L.

AU - El-Fakahany, Esam E.

N1 - Funding Information: Muscarinic acetylcholine receptors mediate various types of biochemical responses such as inhibition of cyclic AMP synthesis, stimulation of cyclic GMP formation as well as phosphoinositide hydrolysis (McKinney and Richelson, 1984; Nathanson, 1987). Data from biochemical and physiological studies have provided insights into the heterogeneity of the muscarinic receptor. For i Supported in part by Grants NS-24158 and AG-07118 from the National Institutes of Health and by Contract DAAG-29-85-K-0123 from the U.S. Army Research Office. 2 Present address: Neuroscience Laboratory, University of Michigan, Ann Arbor, MI, U.S.A. Recipient of an Emerson Fellowship from the University of Maryland during the course of this work. * Recipient of a Research Career Development Award from the National Institutes of Health (AG-00344). To whom all correspondence should be addressed.

PY - 1988/10/26

Y1 - 1988/10/26

N2 - There was a 25 and 27% reduction in the density of mouse brain muscarinic acetylcholine receptors 18 and 24 h following a single injection of the organophosphate diisopropylfluorophosphate (DFP) when the muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) was used as the ligand. Down-regulation of specific [3H]NMS binding was rapidly reversible reaching control levels 36 h after DFP administration. Carbamylcholine and pirenzepine competition for the specific binding of either [3H]NMS or [3H]quinuclidinyl benzilate ([3H]QNB) in brain homogenates from untreated and DFP-treated mice demonstrated that the alteration in muscarinic receptor density following acute DFP treatment was not accompanied by a change in a particular muscarinic receptor binding conformation. Furthermore, the magnitude of muscarinic receptor-mediated phosphoinositide hydrolysis was unchanged following short-term DFP treatment suggesting that a physiological desensitization in this response does not accompany acute down-regulation of [3H]NMS binding sites.

AB - There was a 25 and 27% reduction in the density of mouse brain muscarinic acetylcholine receptors 18 and 24 h following a single injection of the organophosphate diisopropylfluorophosphate (DFP) when the muscarinic antagonist [3H]N-methylscopolamine ([3H]NMS) was used as the ligand. Down-regulation of specific [3H]NMS binding was rapidly reversible reaching control levels 36 h after DFP administration. Carbamylcholine and pirenzepine competition for the specific binding of either [3H]NMS or [3H]quinuclidinyl benzilate ([3H]QNB) in brain homogenates from untreated and DFP-treated mice demonstrated that the alteration in muscarinic receptor density following acute DFP treatment was not accompanied by a change in a particular muscarinic receptor binding conformation. Furthermore, the magnitude of muscarinic receptor-mediated phosphoinositide hydrolysis was unchanged following short-term DFP treatment suggesting that a physiological desensitization in this response does not accompany acute down-regulation of [3H]NMS binding sites.

KW - (Down-regulation)

KW - Di-isopropylfluorophosphate (DFP)

KW - Muscarinic acetylcholine receptor subtypes

KW - Organophosphate

KW - Phosphoinositide metabolism

KW - Pirenzepine

KW - Tolerance

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UR - https://www.scopus.com/pages/publications/0023709154#tab=citedBy

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DO - 10.1016/0014-2999(88)90144-6

M3 - Article

C2 - 2850209

AN - SCOPUS:0023709154

SN - 0014-2999

VL - 156

SP - 35

EP - 45

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1

ER -

Lack of alterations in muscarinic receptor subtypes and phosphoinositide hydrolysis upon acute DFP treatment

Abstract

Bibliographical note

Keywords

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