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Novel Signaling Pathways Mediating Reciprocal Control of Keratinocyte Migration and Wound Epithelialization through M3 and M4 Muscarinic Receptors

Alex I. Chernyavsky, Juan Arredondo, Jürgen Wess, Evert Karlsson and Sergei A. Grando
The Journal of Cell Biology
Vol. 166, No. 2 (Jul. 19, 2004), pp. 261-272
Stable URL: http://www.jstor.org/stable/1622100
Page Count: 12
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Novel Signaling Pathways Mediating Reciprocal Control of Keratinocyte Migration and Wound Epithelialization through  M3 and  M4 Muscarinic Receptors
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Abstract

To test the hypothesis that keratinocyte (KC) migration is modulated by distinct muscarinic acetylcholine (ACh) receptor subtypes, we inactivated signaling through specific receptors in in vitro and in vivo models of reepithelialization by subtype-selective antagonists, small interfering RNA, and gene knockout in mice. KC migration and wound reepithelialization were facilitated by M4 and inhibited by M3. Additional studies showed that M4 increases expression of "migratory" integrins α 5β 1, α vβ 5, and α vβ 6, whereas M3 up-regulates "sedentary" integrins α 2β 1 and α 3β 1. Inhibition of migration by M3 was mediated through Ca2+-dependent guanylyl cyclase-cyclic GMP-protein kinase G signaling pathway. The M4 effects resulted from inhibition of the inhibitory pathway involving the adenylyl cyclase-cyclic AMP-protein kinase A pathway. Both signaling pathways intersected at Rho, indicating that Rho kinase provides a common effector for M3 and M4 regulation of cell migration. These findings offer novel insights into the mechanisms of ACh-mediated modulation of KC migration and wound reepithelialization, and may aid the development of novel methods to promote wound healing.

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