Desensitization of the histamine H1‐receptor and transcriptional down‐regulation of histamine H1‐receptor gene expression in bovine tracheal smooth muscle
JL Pype, JCW Mak, LJ Dupont… - British journal of …, 1998 - Wiley Online Library
JL Pype, JCW Mak, LJ Dupont, GM Verleden, PJ Barnes
British journal of pharmacology, 1998•Wiley Online Library1 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. 2 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 …
H1‐receptors and in the expression of the histamine H1‐receptor gene in airway smooth
muscle. 2 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 …
- 1We 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.
- 2Prolonged 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.
- 3A 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.
- 4Binding 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.
- 5PDBu (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.
- 6Nuclear 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).
- 7In 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
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