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¹ Department of Dermatology, University of California, Davis, Sacramento, CA 95817
² Laboratory of Bioorganic Chemistry, Molecular Signaling Section, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
³ Section of Experimental Geriatrics, Neurotec, Karolinska Institute, 141 86 Huddinge, Sweden

Address correspondence to Sergei A. Grando, Dept. of Dermatology, University of California, Davis, 4860 Y St., #3400, Sacramento, CA 95817. Tel.: (916) 734-6057. Fax: (916) 734-6793. email: sagrando{at}ucdavis.edu

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 ₅ß₁, _Vß₅, and _Vß₆, whereas M₃ up-regulates "sedentary" integrins ₂ß₁ and ₃ß₁. 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.

Key Words: integrins; cyclic GMP; cyclic AMP; knockout mice; acetylcholine

Abbreviations used in this paper: AC, adenylyl cyclase; ACh, acetylcholine; AGKOS, agarose gel keratinocyte outgrowth system; [Ca²⁺]_i, intracellular-free calcium; cGMP, cyclic GMP; GC, guanylyl cyclase; GPCR, G protein–coupled receptor; IF, immunofluorescence; KC, keratinocyte; KGM, KC growth medium; KO, knockout; mAChR, muscarinic ACh receptor; PKA, protein kinase A; PKG, protein kinase G; ROK, Rho-associated protein kinase; siRNA, small interfering RNA; WT, wild-type.

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