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Coupling of ionic events to protein kinase signaling cascades upon activation of alpha7 nicotinic receptor: cooperative regulation of alpha2-integrin expression and Rho kinase activity.

ABSTRACT: Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of keratinocytes (KCs) during wound epithelialization is one of the major goals in epithelial cell biology. The acetylcholine (ACh)-gated ion channels, or nicotinic ACh receptors (nAChRs), mediate the nicotinergic signaling that controls crawling locomotion of KCs. To elucidate relative contributions of the ionic and protein kinase-mediated events elicited due to activation of alpha7 nAChRs, we quantitated expression of alpha2-integrin gene at the mRNA and protein levels and also measured Rho kinase activity in KCs stimulated with the alpha7 agonist AR-R17779 while blocking the Na+ or Ca2+ entry and/or inhibiting signaling kinases. The results demonstrated the existence of the two-component signaling systems coupling the ionic events and protein kinase signaling cascades downstream of alpha7 nAChR to simultaneous up-regulation of alpha2-integrin expression and activation of Rho kinase. The Raf/MEK1/ERK1/2 cascade up-regulating alpha2-integrin was activated due to both Ca2+-dependent recruitment of Ca2+/calmodulin-dependent protein kinase II and protein kinase C and Ca2+-independent activation of Ras. Likewise the phosphatidylinositol 3-kinase-mediated activation of Rho kinase was elicited due to both Ca2+ entry-dependent involvement of Ca2+/calmodulin-dependent protein kinase II and Ca2+-independent activation of Jak2. Thus, although the initial signals emanating from activated alpha7 nAChR are different in nature the pathways intersect at common effector molecules providing for a common end point effect. This novel paradigm of nAChR-mediated coordination of the ionic and metabolic signaling events can allow an auto/paracrine ACh to simultaneously alter gene expression and induce reciprocal changes in the cytoskeleton and contractile system of KCs required to compete a particular step of wound epithelialization.

SUBMITTER: Chernyavsky AI

PROVIDER: S-EPMC2755938 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Coupling of ionic events to protein kinase signaling cascades upon activation of alpha7 nicotinic receptor: cooperative regulation of alpha2-integrin expression and Rho kinase activity.

Chernyavsky Alexander I AI Arredondo Juan J Qian Jing J Galitovskiy Valentin V Grando Sergei A SA

The Journal of biological chemistry 20090623 33

Defining the signaling mechanisms and effector proteins mediating phenotypic and mechanical plasticity of keratinocytes (KCs) during wound epithelialization is one of the major goals in epithelial cell biology. The acetylcholine (ACh)-gated ion channels, or nicotinic ACh receptors (nAChRs), mediate the nicotinergic signaling that controls crawling locomotion of KCs. To elucidate relative contributions of the ionic and protein kinase-mediated events elicited due to activation of alpha7 nAChRs, we ...[more]

PMID: 19549780

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Coupling of ionic events to protein kinase signaling cascades upon activation of alpha7 nicotinic receptor: cooperative regulation of alpha2-integrin expression and Rho kinase activity.

Publications

Coupling of ionic events to protein kinase signaling cascades upon activation of alpha7 nicotinic receptor: cooperative regulation of alpha2-integrin expression and Rho kinase activity.

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