RT Journal Article
SR Electronic
T1 Muscarinic acetylcholine type-3 receptor desensitization due to chronic exposure to Sjögren's syndrome-associated autoantibodies.
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP 296
OP 306
VO 33
IS 2
A1 Seunghee Cha
A1 Eric Singson
A1 Janet Cornelius
A1 Jarajapu P Yagna
A1 Harm J Knot
A1 Ammon B Peck
YR 2006
UL http://www.jrheum.org/content/33/2/296.abstract
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.