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Changes in affinity states during down-regulation of muscarinic receptors in tracheal smooth muscle of organophosphate-treated swine.
J Auton Pharmacol. 1988 Jun; 8(2):79-91.JA

Abstract

1. Subacute (daily) treatment of male swine with the organophosphate acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP) resulted in tolerance to the effects of DFP within 5-6 days. 2. Subacute administration of DFP resulted in a 98% inhibition of tissue cholinesterase after 7 days and in a decrease of [3H]quinuclidinyl benzilate [(3H]QNB) binding sites in homogenates of tracheal smooth muscle by 77%. The maximal density of receptors (Bmax) decreased from 1.8 +/- 0.4 to 0.5 +/- 0.1 pmole mg-1 protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding. 3. Pirenzepine displacement of [3H]QNB binding was best described by a single binding site model, with a Ki of 230 +/- 40 nM. This value was unchanged following seven days of DFP treatment (250 +/- 30 nM). The low affinity for this M1 antagonist suggests that there is predominantly a single population of [3H]QNB binding sites of the M2 subtype in tracheal smooth muscle. 4. Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 210 +/- 60 microM (61 +/- 1%) and KiH = 1.2 +/- 0.4 microM (39 +/- 1%) respectively (n = 7) for the low and high affinity states. Seven-day treatment with DFP reduced the percent of high affinity receptors to 25 +/- 4%. 5. Addition of Mg++ to the incubation medium prevented this shift in the proportion of low and high affinity receptors. Gpp(NH)p and Mg++ together decreased the proportion of the high affinity receptors when added to the incubation medium in control tissue (to 25%), but not tissue from 7-day DFP-treated swine. NEM increased the proportion of muscarinic receptors in the high affinity state both for controls and for the DFP-treated swine, in both cases yielding receptors with identical binding properties. 6. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the affinity of the receptors for agonists 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.
Mohan PM
No affiliation info available
Dwyer TM
No affiliation info available
Farley JM
No affiliation info available

MeSH

AnimalsCarbacholEthylmaleimideGuanylyl ImidodiphosphateIn Vitro TechniquesIsoflurophateMagnesiumMaleQuinuclidinyl BenzilateReceptors, MuscarinicSwineTrachea

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

3170629

Citation

Yang, C M., et al. "Changes in Affinity States During Down-regulation of Muscarinic Receptors in Tracheal Smooth Muscle of Organophosphate-treated Swine." Journal of Autonomic Pharmacology, vol. 8, no. 2, 1988, pp. 79-91.
Yang CM, Mohan PM, Dwyer TM, et al. Changes in affinity states during down-regulation of muscarinic receptors in tracheal smooth muscle of organophosphate-treated swine. J Auton Pharmacol. 1988;8(2):79-91.
Yang, C. M., Mohan, P. M., Dwyer, T. M., & Farley, J. M. (1988). Changes in affinity states during down-regulation of muscarinic receptors in tracheal smooth muscle of organophosphate-treated swine. Journal of Autonomic Pharmacology, 8(2), 79-91.
Yang CM, et al. Changes in Affinity States During Down-regulation of Muscarinic Receptors in Tracheal Smooth Muscle of Organophosphate-treated Swine. J Auton Pharmacol. 1988;8(2):79-91. PubMed PMID: 3170629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Changes in affinity states during down-regulation of muscarinic receptors in tracheal smooth muscle of organophosphate-treated swine. AU - Yang,C M, AU - Mohan,P M, AU - Dwyer,T M, AU - Farley,J M, PY - 1988/6/1/pubmed PY - 1988/6/1/medline PY - 1988/6/1/entrez SP - 79 EP - 91 JF - Journal of autonomic pharmacology JO - J Auton Pharmacol VL - 8 IS - 2 N2 - 1. Subacute (daily) treatment of male swine with the organophosphate acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP) resulted in tolerance to the effects of DFP within 5-6 days. 2. Subacute administration of DFP resulted in a 98% inhibition of tissue cholinesterase after 7 days and in a decrease of [3H]quinuclidinyl benzilate [(3H]QNB) binding sites in homogenates of tracheal smooth muscle by 77%. The maximal density of receptors (Bmax) decreased from 1.8 +/- 0.4 to 0.5 +/- 0.1 pmole mg-1 protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding. 3. Pirenzepine displacement of [3H]QNB binding was best described by a single binding site model, with a Ki of 230 +/- 40 nM. This value was unchanged following seven days of DFP treatment (250 +/- 30 nM). The low affinity for this M1 antagonist suggests that there is predominantly a single population of [3H]QNB binding sites of the M2 subtype in tracheal smooth muscle. 4. Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 210 +/- 60 microM (61 +/- 1%) and KiH = 1.2 +/- 0.4 microM (39 +/- 1%) respectively (n = 7) for the low and high affinity states. Seven-day treatment with DFP reduced the percent of high affinity receptors to 25 +/- 4%. 5. Addition of Mg++ to the incubation medium prevented this shift in the proportion of low and high affinity receptors. Gpp(NH)p and Mg++ together decreased the proportion of the high affinity receptors when added to the incubation medium in control tissue (to 25%), but not tissue from 7-day DFP-treated swine. NEM increased the proportion of muscarinic receptors in the high affinity state both for controls and for the DFP-treated swine, in both cases yielding receptors with identical binding properties. 6. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the affinity of the receptors for agonists which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor. SN - 0144-1795 UR - https://www.unboundmedicine.com/medline/citation/3170629/Changes_in_affinity_states_during_down_regulation_of_muscarinic_receptors_in_tracheal_smooth_muscle_of_organophosphate_treated_swine_ DB - PRIME DP - Unbound Medicine ER -