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


CONCLUSIONS
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.
Cha
Seunghee
S
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, 32610, USA.
Singson
Eric
E
Cornelius
Janet
J
Yagna
Jarajapu P
JP
Knot
Harm J
HJ
Peck
Ammon B
AB
D000818:Animals; D019138:Antibodies, Blocking / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018727:Muscarinic Antagonists / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects; D010862:Pilocarpine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000276:immunology*; D012859:Sjogren's Syndrome / Q000097:blood / Q000276:immunology* / Q000473:pathology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
D019138:Antibodies, Blocking; D001323:Autoantibodies; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D002217:Carbachol