Normal liver function depends upon rapid and precise movement of ions and other solutes across the plasma membrane of each cell at rates greater that 1010 ions sec -1. Both the number and types of ions are regulated on a minute-to-minute basis to meet changing physiologic demands caused by circulating hormones, substrate availability, or metabolic stress. These dynamic changes in transport directly influence transmembrane water movement and liver cell volume. Indeed, hormone- induced cell volume increases have recently been recognized to be a potent signal, regulating liver function through effects on cellular kinases, gene expression, bile formation, and exocytosis. The studies described in this proposal will evaluate the mechanisms that couple cell metabolism, ion transport, and cell volume by addressing the Working Hypothesis that intra- and extracellular signals regulate cell volume through dynamic modulation of Na+ influx through opening of cation- selective channels, a stimulus for cell volume increases, and K+ and Cl- efflux, a stimulus for cell volume decreases.
The Specific Aims are i) to evaluate the role of extracellular ATP as an autocrine/paracrine signaling molecule mediating recovery from cell swelling; ii) to assess the physiologic roles and targets of protein kinase C and phosphoinositide 3-kinase as intracellular signaling molecules transducing cell volume changes to channel regulation; iii) to determine the molecular basis of volume-sensitive Cl- efflux, and iv) to identify the channels and regulatory mechanisms governing Na+ influx and recovery from cell shrinkage. The channels and signaling pathways addressed in these studies represent essential sites of action for hormones and other signals that utilize cell volume as an intermediary signal to modulate liver metabolic and secretory functions. In addition, definition of the mechanisms involved may provide new strategies for treatment of liver injury under conditions where cell volume regulation is impaired, including alcohol toxicity, ischemia, and liver inflammation.
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