PT  - JOURNAL ARTICLE
AU  - Seunghee Cha
AU  - Eric Singson
AU  - Janet Cornelius
AU  - Jarajapu P Yagna
AU  - Harm J Knot
AU  - Ammon B Peck
TI  - Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.
DP  - 2006 Feb 01
TA  - The Journal of Rheumatology
PG  - 296--306
VI  - 33
IP  - 2
4099  - http://www.jrheum.org/content/33/2/296.short
4100  - http://www.jrheum.org/content/33/2/296.full
SO  - J Rheumatol2006 Feb 01; 33
AB  - 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.