Abstract
Activation of the inositol lipid signaling system results in cytosolic Ca2+ oscillations and intra- and intercellular Ca2+ waves in many isolated cell preparations. However, this form of temporal and spatial organization of signaling has not been demonstrated in intact tissues. Digital imaging fluorescence microscopy was used to monitor Ca2+ at the cellular and subcellular level in intact perfused rat liver loaded with fluorescent Ca2+ indicators. Perfusion with low doses of vasopressin induced oscillations of hepatocyte Ca2+ that were coordinated across entire lobules of the liver by propagation of Ca2+ waves along the hepatic plates. At the subcellular level these periodic Ca2+ waves initiated from the sinusoidal domain of cells within the periportal region and propagated radially across cell-cell contacts into the pericentral region, or until terminated by annihilation collision with other Ca2+ wave fronts. With increasing agonist dose, the frequency but not the amplitude of the Ca2+ waves increased. Intracellular Ca2+ wave rates were constant, but transcellular signal propagation was determined by agonist dose, giving rise to a dose-dependent increase in the rate at which Ca2+ waves spread through the liver. At high vasopressin doses, a single Ca2+ wave was observed and the direction of Ca2+ wave propagation was reversed, initiating in the pericentral region and spreading to the periportal region. It is concluded that intercellular Ca2+ waves may provide a mechanism to coordinate responses across the functional units of the liver.
Highlights
Grants DK38422 and AA07215 and Training Grant T32-AA07463
Infusion of vasopressin resulted in increases of [Ca2+]i, which occurred first in a limited number ofhepatocytes in each lobule and spread progressively through adjacent cells
The rate of rise and maximum amplitude of [Ca2+l increase within each cell was the same for all agonist doses, and the calibrated [Ca2+]i values were somewhat lower than we calculated for isolated hepatocytes, the rise time was very similar (2-6 s)
Summary
Vol 270, No 14, Issue of April 7, pp. 8102-8107, 1995 Printed in U.s.A. Coordination of Ca2 + Signaling by Intercellular Propagation of Ca2 + Waves in the Intact Liver*. Activation of the inositol lipid signaling system results in cytosolic Ca2 + oscillations and intra- and intercellular Ca2 + waves in many isolated cell preparations This form of temporal and spatial organization of signaling has not been demonstrated in intact tissues. [Ca2 +]i wave propagation is not an automatic consequence of the existence of a syncytium, since monolayers of epithelial or glial cells, which propagate intercellular [Ca2 +J; waves when stimulated mechanically, demonstrate asynchronous [Ca2+]i oscillations that do not propagate into neighboring cells [10, 11] Another property of [Ca2 +]i oscillations observed in isolated cells that may be regulated differently in intact tissues is the control of oscillation frequency by agonist dose. Frequency modulation of [Ca2 +]i oscillations has been proposed to play an important role in determining the extent and targeting of cellular [Ca2 +J; responses [1, 14]
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