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Abstract

Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.

Seunghee Cha, Eric Singson, Janet Cornelius, Jarajapu P Yagna, Harm J Knot and Ammon B Peck
The Journal of Rheumatology February 2006, 33 (2) 296-306;
Seunghee Cha
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Eric Singson
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Janet Cornelius
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Jarajapu P Yagna
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Harm J Knot
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Ammon B Peck
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Abstract

OBJECTIVE: Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been shown to inhibit M3R-mediated responses by both in vitro contractility and fura-2 microfluorimetry analyses of intracellular calcium mobilization, suggesting an important role for anti-M3R autoantibody in secretory dysfunction. We investigated whether chronic stimulation of M3R by anti-M3R autoantibodies and/or the agonist pilocarpine results in a general M3R desensitization. METHODS: Carbachol-evoked responses of mouse-bladder smooth muscle strips were measured following exposure to anti-M3R-positive and/or anti-M3R-negative sera from either NOD/Lt mice, a model of SS-like disease, or human patients with primary SS. RESULTS: Bladder smooth muscle strips isolated from NOD/Lt mice with circulating anti-M3R autoantibodies exhibited lower carbachol-evoked responses than smooth muscle strips from anti-M3R autoantibody-negative NOD/Lt mice and control C57BL/6 mice. Repeated pilocarpine injections of NOD mice for 6 days also revealed M3R desensitization in the agonist-evoked contractile assay, whereas age and sex matched C57BL/6 mice injected with pilocarpine for the same period showed a 2-fold higher response. Incubation of smooth muscle strips with sera obtained from patients with primary SS resulted in both stimulated and inhibited responses. CONCLUSION: These results support the hypothesis that chronic stimulation of membrane-bound M3R can result in receptor desensitization, and raise questions about repeated use of pilocarpine by patients positive for anti-M3R autoantibodies.

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The Journal of Rheumatology
Vol. 33, Issue 2
1 Feb 2006
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Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.
Seunghee Cha, Eric Singson, Janet Cornelius, Jarajapu P Yagna, Harm J Knot, Ammon B Peck
The Journal of Rheumatology Feb 2006, 33 (2) 296-306;

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Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.
Seunghee Cha, Eric Singson, Janet Cornelius, Jarajapu P Yagna, Harm J Knot, Ammon B Peck
The Journal of Rheumatology Feb 2006, 33 (2) 296-306;
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