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J. Biol. Chem., Vol. 283, Issue 6, 3401-3408, February 8, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/6/3401    most recent M704956200v2 M704956200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chernyavsky, A. I. Articles by Grando, S. A. Search for Related Content PubMed PubMed Citation Articles by Chernyavsky, A. I. Articles by Grando, S. A. Social Bookmarking                      What's this?

Differential Coupling of M₁ Muscarinic and 7 Nicotinic Receptors to Inhibition of Pemphigus Acantholysis^*

Alex I. Chernyavsky, Juan Arredondo, Timothy Piser, Evert Karlsson^¶, and Sergei A. Grando¹

From the Department of Dermatology, University of California, Irvine, California 92697, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850, and the ^¶Karolinska Institute, Lindsbergsgatan 11A, Uppsala 752 40, Sweden

The mechanisms mediating and regulating assembly and disassembly of intercellular junctions is a subject of intensive research. The IgG autoantibodies produced in patients with the immunoblistering skin disease pemphigus vulgaris (PV) can induce keratinocyte (KC) dyshesion (acantholysis) via mechanisms that involve signaling kinases targeting intercellular adhesion molecules, thus providing a useful model to study the physiologic regulation of KC cohesion. Previous studies showed that activation of Src and protein kinase C are the earliest events in the PV IgG-induced intracellular phosphorylation cascades and that cholinergic agonists are effective for treating patients with pemphigus. In this study, we sought to elucidate the molecular mechanisms allowing cholinergic agonists to inhibit PV IgG-induced acantholysis and phosphorylation of KC adhesion molecules. The extent of acantholysis in KC monolayers correlated closely with the degree of PV IgG-induced phosphorylation of p120- and β-catenins, with classic isoforms of protein kinase C mediating serine phosphorylation of β-catenin and Src-tyrosine phosphorylation of p120-catenin. The M₁ muscarinic agonist pilocarpine blocked phosphorylation of both catenins, which could be abolised by the M₁ antagonist MT7. The 7 nicotinic agonist AR-R17779 inhibited phosphorylation of P120-cateinin. The 7 antagonist methyllycaconitine abolished the effect of AR-R17779. Okadaic acid abrogated protective effects of agonists on phosphorylation of β-catenin, and pervanadate, on that of p120-catenin. Stimulation of KCs with pilocarpine significantly (p < 0.05) elevated both serine/threonine and tyrosine phosphatase activities in KCs. AR-R17779 both stimulated tyrosine phosphatase and decreased PV IgG-induced Src activity. Methyllycaconitine released Src activity in intact KCs and caused acantholysis. Thus, downstream signaling from M₁ abolished PV IgG-dependent catenin phosphorylation due to activation of both serine/threonine and tyrosine phosphatases, whereas 7 action involved both activation of tyrosine phosphatase and inhibition of Src. These findings identified novel paradigm of regulation of signaling kinases associated with cholinergic receptors and provided mechanistic explanation of therapeutic activity of cholinomimetics in PV patients.

Received for publication, June 15, 2007 , and in revised form, December 10, 2007.

^* This work was supported in part by National Institutes of Health Grant GM62136 and the International Pemphigus Research Fund (to S. A. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Dermatology, University of California Irvine, C340 Medical Science I, Irvine, CA 92697. Tel.: 949-824-2713; Fax: 949-824-2993; E-mail: sgrando{at}uci.edu.

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				E. Schmidt, J. Gutberlet, D. Siegmund, D. Berg, H. Wajant, and J. Waschke Apoptosis is not required for acantholysis in pemphigus vulgaris Am J Physiol Cell Physiol, January 1, 2009; 296(1): C162 - C172. [Abstract] [Full Text] [PDF]