RECEPTOR-ORIENTED INTERCELLULAR CALCIUM WAVES EVOKED BY VASOPRESSIN IN RAT HEPATOCYTES

Agonist-induced intracellular calcium signals may propagate as interce llular Ca2+ waves in multicellular systems as well as in intact organs . The mechanisms initiating intercellular Ca2+ waves in one cell and d etermining their direction are unknown. We investigated these mechanis ms directly on fura2-loaded multicellular systems of rat hepatocytes a nd on cell populations issued from peripheral (periportal) and central (perivenous) parts of the hepatic lobule. There was a gradient in vas opressin sensitivity along connected cells as demonstrated by low vaso pressin concentration challenge. Interestingly, the intercellular sens itivity gradient was abolished either when D-myoinositol 1,4,5-trispho sphate (InsP(3)) receptor was directly stimulated after hash photolysi s of caged InsP(3) or when G proteins were directly stimulated with Al F4-. The gradient in vasopressin sensitivity in multiplets was correla ted with a heterogeneity of vasopressin sensitivity in the hepatic lob ule. There were more vasopressin-binding sites, vasopressin-induced In sP(3) production and Via vasopressin receptor mRNAs in perivenous than in periportal cells. Therefore, we propose that hormone receptor dens ity determines the cellular sensitivity gradient from the peripheral t o the central zones of the liver cell plate, thus the starting cell an d the direction of intercellular Ca2+ waves, leading to directional ac tivation of Ca2+-dependent processes.