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Desensitization of the histamine H1‐receptor and transcriptional down‐regulation of histamine H1‐receptor gene expression in bovine tracheal smooth muscle

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Title: Desensitization of the histamine H1‐receptor and transcriptional down‐regulation of histamine H1‐receptor gene expression in bovine tracheal smooth muscle
Authors: Pype, JL, Mak, JCW, Dupont, LJ, Verleden, GM, Barnes, PJ
Source: British Journal of Pharmacology. 125:1477-1484
Publisher Information: Wiley, 1998.
Publication Year: 1998
Subject Terms: 0301 basic medicine, Trachea - Metabolism, Indoles, Enzyme Inhibitors - Pharmacology, Inositol Phosphates, Down-Regulation, Gene Expression Regulation - Drug Effects, In Vitro Techniques, Tritium, Muscle Contraction - Drug Effects, Indoles - Pharmacology, Dose-Response Relationship, Inositol Phosphates - Metabolism, Maleimides, 03 medical and health sciences, Maleimides - Pharmacology, Genetic - Drug Effects, Receptors, Transcription, Genetic - Drug Effects, Animals, Northern, Receptors, Histamine H1, Smooth - Drug Effects - Metabolism, Enzyme Inhibitors, Phorbol 12,13-Dibutyrate, Protein Kinase C, 0303 health sciences, Histamine H1 - Genetics - Metabolism, Dose-Response Relationship, Drug, Blotting, Receptors, Histamine H1 - Genetics - Metabolism, Muscle, Smooth, Protein Kinase C - Antagonists & Inhibitors - Metabolism, Blotting, Northern, Enzyme Activation, Trachea, Sodium Fluoride - Pharmacology, Gene Expression Regulation, Muscle, Sodium Fluoride, Cattle, Drug, Transcription, Phorbol 12,13-Dibutyrate - Pharmacology, Muscle, Smooth - Drug Effects - Metabolism, Histamine, Muscle Contraction
Description: We have investigated the role of protein kinase C (PKC) in the desensitization of histamine H1‐receptors and in the expression of the histamine H1‐receptor gene in airway smooth muscle. Prolonged 4β‐phorbol 12,13 dibutyrate (PDBu) pretreatment (4 h, 100 nm–1 μm) of bovine trachealis caused a concentration‐dependent loss of contraction in response to histamine H1‐receptor stimulation, which was associated with a concentration‐dependent decrease in histamine‐induced total [3H]‐inositol phosphates accumulation. In contrast, the responses to sodium fluoride, a direct G‐protein activator, were unalterd by PDBu (100–300 nm) pre‐incubation and only slightly reduced following incubation with 1 μm PDBu. A selective PKC inhibitor, GF 109203X, partially blocked the PDBu (1 μm)‐induced desensitization and completely blocked the effect of 100 nm PDBu, confirming the involvement of PKC. Binding experiments using [3H]‐pyrilamine revealed a class of high‐affinity binding sites within the range for the histamine H1 receptor in airway smooth muscle. PDBu (1 μm) pretreatment for 4 h did not change the number of histamine H1 receptors. PDBu (1 μm) exposure caused a time‐dependent reduction in the steady‐state levels of histamine H1‐receptor mRNA, which was inhibited by pre‐incubation with GF 109203X and by cycloheximide, a protein synthesis inhibitor. Nuclear run‐on assays revealed a 50% reduction in the rate of histamine H1‐receptor gene transcription after 17 h PDBu pretreatment, whereas mRNA stability was not affected by PDBu pretreatment (17 h). In conclusion, we have shown a PKC‐mediated desensitization of the histamine H1‐receptor in BTSM and a transcriptional down‐regulation of the histamine H1‐receptor gene expression, which requires new protein synthesis. British Journal of Pharmacology (1998) 125, 1477–1484; doi:10.1038/sj.bjp.0702222
Document Type: Article
Language: English
ISSN: 1476-5381
0007-1188
DOI: 10.1038/sj.bjp.0702222
Access URL: https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1038/sj.bjp.0702222
https://pubmed.ncbi.nlm.nih.gov/9884076
https://core.ac.uk/display/34445122
http://hub.hku.hk/handle/10722/162216
http://doi.wiley.com/10.1038/sj.bjp.0702222
http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0702222/abstract
https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0702222
https://onlinelibrary.wiley.com/doi/abs/10.1038/sj.bjp.0702222
http://hdl.handle.net/10722/162216
Rights: Wiley Online Library User Agreement
Accession Number: edsair.doi.dedup.....4a6381c76faee4c3ec45b7bd984fc855
Database: OpenAIRE
Description
Abstract:We have investigated the role of protein kinase C (PKC) in the desensitization of histamine H1‐receptors and in the expression of the histamine H1‐receptor gene in airway smooth muscle. Prolonged 4β‐phorbol 12,13 dibutyrate (PDBu) pretreatment (4 h, 100 nm–1 μm) of bovine trachealis caused a concentration‐dependent loss of contraction in response to histamine H1‐receptor stimulation, which was associated with a concentration‐dependent decrease in histamine‐induced total [3H]‐inositol phosphates accumulation. In contrast, the responses to sodium fluoride, a direct G‐protein activator, were unalterd by PDBu (100–300 nm) pre‐incubation and only slightly reduced following incubation with 1 μm PDBu. A selective PKC inhibitor, GF 109203X, partially blocked the PDBu (1 μm)‐induced desensitization and completely blocked the effect of 100 nm PDBu, confirming the involvement of PKC. Binding experiments using [3H]‐pyrilamine revealed a class of high‐affinity binding sites within the range for the histamine H1 receptor in airway smooth muscle. PDBu (1 μm) pretreatment for 4 h did not change the number of histamine H1 receptors. PDBu (1 μm) exposure caused a time‐dependent reduction in the steady‐state levels of histamine H1‐receptor mRNA, which was inhibited by pre‐incubation with GF 109203X and by cycloheximide, a protein synthesis inhibitor. Nuclear run‐on assays revealed a 50% reduction in the rate of histamine H1‐receptor gene transcription after 17 h PDBu pretreatment, whereas mRNA stability was not affected by PDBu pretreatment (17 h). In conclusion, we have shown a PKC‐mediated desensitization of the histamine H1‐receptor in BTSM and a transcriptional down‐regulation of the histamine H1‐receptor gene expression, which requires new protein synthesis. British Journal of Pharmacology (1998) 125, 1477–1484; doi:10.1038/sj.bjp.0702222
ISSN:14765381
00071188
DOI:10.1038/sj.bjp.0702222