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An aqueous extract of Poncirus fructus activates the prokinetic activity of 5-HT receptor subtype 4 without hERG interaction
- Source :
- Journal of ethnopharmacology. 132(1)
- Publication Year :
- 2010
-
Abstract
- Aim of the study Poncirus fructus (PF) – also known as the dried, immature fruit of Poncirus trifoliata (L.) Raf. (Rutaceae) – is a natural substance that has long been used for various gastrointestinal disorders in eastern Asia. An aqueous extract of PF (PF-W) has particularly potent gastroprokinetic effects, but its molecular mechanism was not well understood. Identification of the underlying prokinetic mechanism of PF-W was pursued in the present study. Materials and methods Changes in in vitro cAMP levels and in vivo intestinal transit rate (ITR) caused by PF-W were measured after pretreatment with GR125487, an antagonist for serotonin receptor subtype 4 (5-HT4R). An [ 3 H] astemizole binding assay and electrophysiology experiments were performed to determine if PF-W has any interaction with the human ether-a-go-go related gene (hERG) potassium channel. Results PF-W induced an increase in intracellular cAMP in 5-HT4R-expressing HEK293T cells, indicating that PF-W does activate 5-HT4R. Moreover, pretreatment with GR125487 successfully blocked the increase, suggesting that the response was 5-HT4R-specific. More importantly, pretreatment of GR125487 in rats inhibited the elevation of ITR by PF-W, indicating that the prokinetic effect of PF-W was indeed exerted via 5-HT4R. On the other hand, both [ 3 H]-astemizole binding assay and electrophysiological experiments revealed that PF-W did not interfere at all with the hERG channel. Conclusion It was found that PF-W exerts its prokinetic activity through a 5-HT4R-mediated pathway, with no interaction with hERG channels. Therefore, PF-W is a good candidate that might be developed as a prokinetic agent with fewer expected cardiac side effects.
- Subjects :
- ERG1 Potassium Channel
Serotonin 5-HT4 Receptor Antagonists
Patch-Clamp Techniques
medicine.medical_treatment
hERG
Prokinetic agent
Pharmacology
Transfection
Cell Line
Rats, Sprague-Dawley
Serotonin 5-HT4 Receptor Agonists
In vivo
Drug Discovery
medicine
Cyclic AMP
Potassium Channel Blockers
Animals
Humans
Poncirus
Receptor
Gastrointestinal Transit
5-HT receptor
biology
Plant Extracts
Cell Membrane
Antagonist
Astemizole
Potassium channel
Ether-A-Go-Go Potassium Channels
Rats
Fruit
biology.protein
Receptors, Serotonin, 5-HT4
medicine.drug
Protein Binding
Subjects
Details
- ISSN :
- 18727573
- Volume :
- 132
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of ethnopharmacology
- Accession number :
- edsair.doi.dedup.....89c99649d1706c987ec055defcea8bca