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- W4225420281 abstract "Recent advances in biosensor and optically based techniques have provided a map of the subcellular regions that dictate myocyte behavior. Microdomain level changes of cyclic adenosine 3'5' monophosphate (cAMP) signaling are known to impact the progression of cardiovascular disease. Yet, tools to direct these site-specific interactions are limited. To address this issue, we have applied a set of optogenetic protein species with the spatiotemporal resolution necessary to direct cAMP signaling at distinct intracellular sites. We hypothesize that applying these proteins to a cardiac cell system will help resolve the relationship between cAMP microdomain signaling and cardiac cell behavior. Photoactivation studies have been conducted using optogenetic analogues of adenylate cyclase and protein kinase A (PKA) in the H9c2 cell model. Expression and subcellular localization of these light responsive proteins is characterized by live cell microscopy in this cardiac cell line. Site-specific impacts of signaling are quantified using a genetically encoded PKA activity biosensor as well as pharmacological agonists/antagonists for cAMP signaling mediators and effectors. Results indicate that global cAMP production, through a light activatable adenylate cyclase (bPAC), leads to phosphorylation of a PKA reporter anchored at the outer mitochondrial membrane and plasma membrane. Reporters with nuclear localization do not show this phosphorylation. Experiments validate the expression and recruitment of a light directed protein kinase A 'optogenetic switch' analog in cardiac cells. The expression and recruitment are confirmed with live cell microscopy and demonstrate a unique ability to direct PKA activity and retention to specific intracellular subdomains. The impact of this signaling on microdomain organization as well as the site-specific impacts of light directed PKA microdomain recruitment on cell proliferation, size as a function of biomass, and cell viability compared are considered. This is done in relationship to non illuminated (dark) and catalytically dead optogenetic protein analog controls. We conclude from these results that light directed signaling in cardiac myocytes can provide a site-specific view of intracellular signaling cascades. The application of this approach represents a 'first step' in creating therapies that address the microdomain signaling disruptions associated with cardiac disease." @default.
- W4225420281 created "2022-05-05" @default.
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- W4225420281 date "2022-05-01" @default.
- W4225420281 modified "2023-10-14" @default.
- W4225420281 title "Mapping myocyte microdomains with optogenetic cAMP signaling" @default.
- W4225420281 doi "https://doi.org/10.1096/fasebj.2022.36.s1.r2537" @default.
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