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Vol. 297, Issue 2, 718-726, May 2001

Molecular and Pharmacological Characterization of Muscarinic Receptor Subtypes in a Rat Parotid Gland Cell Line: Comparison with Native Parotid Gland

Charles S. Bockman, Michael E. Bradley, Herbert K. Dang, Wanyun Zeng, Margaret A. Scofield and Frank J. Dowd

Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska

The molecular and pharmacological characteristics of muscarinic receptor subtypes in the rat parotid acinar cell line, PAR-C5, were determined and compared with native rat parotid glands to evaluate the PAR-C5 cell line as a model to study receptor-mediated secretion. Reverse transcription-polymerase chain reaction (RT-PCR) identified mRNAs for M3, M4, and M5 receptor subtypes in both PAR-C5 cells and parotid glands. Specific [N-methyl-3H]scopolamine binding in PAR-C5 and parotid membranes was to a single class of sites with mean KD values of 0.38 and 0.64 nM, respectively. Binding affinities (KI values) of muscarinic receptor subtype-selective drugs were obtained in side-by-side experiments comparing PAR-C5 cells with parotid glands. Nonlinear regression analysis indicated that competition binding curves for drugs in PAR-C5 cells and parotid glands fit best to a one-site binding model. KI values (nM) in PAR-C5 cells and parotid glands, respectively, for atropine (1.0, 2.1), darifenacin (1.2, 2.0), 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (2.9, 2.4), tripitramine (220, 180), pirenzepine (320, 720), and methoctramine (1400, 1700) were consistent with their known affinities at the M3 receptor subtype. Affinities (KB values) of muscarinic receptor subtype-selective drugs for blocking methacholine-stimulated Ca2+ mobilization were determined to show which subtype mediates Ca2+-dependent secretion in Fura-2-loaded PAR-C5 cells. KB values (nM) for atropine (0.44), 4-DAMP (0.38), pirenzepine (140), and methoctramine (320) for blocking Ca2+ responses correlated well with their known affinities at the M3 receptor (r2 = 0.99). These results show that at the level of mRNA, receptor protein and function, PAR-C5 cells and parotid glands are similar, establishing PAR-C5 cells as an important model for muscarinic receptor-mediated secretion.

0022-3565/01/2972-0718$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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