| Serotonin-2 (5-HT2) receptor-mediated signal transduction in human ciliary muscle cells: role in ocular hypotension. | |
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MedLine Citation:
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PMID: 17238805 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE AND METHODS: The aim of this study was to characterize the serotonin (5-hydroxytryptamine; 5-HT) receptors that mediate phosphoinositide (PI) hydrolysis and intracellular Ca2+ ([Ca2+]i) mobilization in isolated cells of human ciliary muscle (h-CM) from multiple donors using a variety of agonists and antagonists. An additional aim was to visualize the mRNAs and receptor binding sites for 5-HT2 receptors in human ciliary body (h-CB), CM, and other tissues by reverse transcriptase polymerase chain reaction and quantitative autoradiography techniques, respectively, and to correlate with ocular hypotensive activity of such compounds. RESULTS: CBs isolated from several donor eyes revealed the presence of 5-HT(2A2C) receptor mRNAs. [3H]-5-HT and [3H]-ketanserin autoradiography on sections of human eyes revealed a high density of 5-HT2 receptor binding sites in the iris, ciliary epithelium, and longitudinal CM. In isolated h-CM cells, the agonists alpha-methyl-5-HT (EC50=63+/-17 nM), 5-HT (EC50=85+/-16 nM), (R)-DOI (EC50=165+/-47 nM), and 5-methoxy alpha-methyl tryptamine (EC50=1200+/-270 nM) differentially stimulated PI turnover. These agonists also mobilized [Ca2+]i in h-CM cells with the following potencies (EC50s): 5-methoxy-tryptamine=42+/-11 nM; alpha-methyl-5-HT=36+/-11 nM; (R)-DOI=120 nM; 5-HT=130+/-36 nM; MK-212=470 nM; mCPP>1 microM; BW723C86=1766 nM. The agonist-induced [Ca2+]i mobilization in h-CM cells was potently blocked by the 5-HT2A-selective antagonist M-100907 (IC50=1.2+/-0.4 nM) but less potently by the antagonists for 5-HT2B (RS-127445, IC50>10 microM) and 5-HT2C (RS-102221, IC50=5.8+/-2.3 microM) receptors. CONCLUSIONS: In conclusion, h-CB, h-CM, and CM cells express mRNAs and proteins for 5-HT2 receptor subtypes, of which the predominant functionally active subtype is the 5-HT2A receptor, as defined by agonist and antagonist activities. These receptors may be responsible for mediating the intraocular pressure reduction observed in recent literature with a number of 5-HT2 agonists, such as (R)-DOI, alpha-methyl-5HT, and AL-34662. |
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Authors:
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Najam A Sharif; Curtis R Kelly; Julie Y Crider; Terry L Davis |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics Volume: 22 ISSN: 1080-7683 ISO Abbreviation: J Ocul Pharmacol Ther Publication Date: 2006 Dec |
Date Detail:
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Created Date: 2007-01-22 Completed Date: 2007-02-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9511091 Medline TA: J Ocul Pharmacol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 389-401 Citation Subset: IM |
Affiliation:
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Ophthalmology Discovery Research, Alcon Research, Ltd., Fort Worth, TX 76134-2099, USA. naj.sharif@alconlabs.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Aged, 80 and over Autoradiography Binding Sites Calcium / metabolism Cell Culture Techniques Cells, Cultured Ciliary Body / cytology, metabolism* Female Humans Male Middle Aged Muscle Cells / metabolism* Ocular Hypertension* / etiology, metabolism Protein Binding Receptors, Serotonin, 5-HT2 / biosynthesis* Reverse Transcriptase Polymerase Chain Reaction Signal Transduction* |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Serotonin, 5-HT2; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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