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Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine.
Toxicol Appl Pharmacol. 1990 Jul; 104(3):375-85.TA

Abstract

Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [(3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.

Authors+Show Affiliations

Yang CM
Department of Pharmacology/Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Dwyer TM
No affiliation info available
Mohan PM
No affiliation info available
Ho IK
No affiliation info available
Farley JM
No affiliation info available

MeSH

AcetylcholinesteraseAnimalsBinding SitesBinding, CompetitiveCarbacholCorpus StriatumDown-RegulationGuanylyl ImidodiphosphateIsoflurophateMagnesiumMalePirenzepineQuinuclidinesQuinuclidinyl BenzilateReceptors, MuscarinicRegression AnalysisSwine

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

2385834

Citation

Yang, C M., et al. "Down-regulation of Muscarinic Receptors in the Striatum of Organophosphate-treated Swine." Toxicology and Applied Pharmacology, vol. 104, no. 3, 1990, pp. 375-85.
Yang CM, Dwyer TM, Mohan PM, et al. Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine. Toxicol Appl Pharmacol. 1990;104(3):375-85.
Yang, C. M., Dwyer, T. M., Mohan, P. M., Ho, I. K., & Farley, J. M. (1990). Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine. Toxicology and Applied Pharmacology, 104(3), 375-85.
Yang CM, et al. Down-regulation of Muscarinic Receptors in the Striatum of Organophosphate-treated Swine. Toxicol Appl Pharmacol. 1990;104(3):375-85. PubMed PMID: 2385834.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine. AU - Yang,C M, AU - Dwyer,T M, AU - Mohan,P M, AU - Ho,I K, AU - Farley,J M, PY - 1990/7/1/pubmed PY - 1990/7/1/medline PY - 1990/7/1/entrez SP - 375 EP - 85 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 104 IS - 3 N2 - Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [(3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/2385834/Down_regulation_of_muscarinic_receptors_in_the_striatum_of_organophosphate_treated_swine_ DB - PRIME DP - Unbound Medicine ER -

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