REGULATION OF INTRACELLULAR PH BY CELL-CELL ADHESIVE INTERACTIONS

As was shown in our previous work, the intracellular pH (pH(i)) of cultured human fibroblasts depends on cell density, The pH(i) is low in single cells, higher in cells, forming small groups and maximal in a sparse monolayer, On the other hand, the pH(i) is low in areas of confluent monolayers. In the present work, we show that the effects of inhibitors of various pH-controlling mechanisms as well as inhibitors of key enzymes in signal transduction pathways depend on the local cell density, We have found that N-ethylhnaleimide and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole, known as inhibitors of V-type H+ ATPase, inhibit the elevation of pH(i) induced by cell-cell contact interactions; meanwhile Cd2+ ions, which inhibit H+ conductive pathway, cause an increase of pH(i) in a confluent monolayer, Our data revealed also that the Na+/H+ antiporter does not play an essential role in the pH(i) regulation by intercellular contacts. Inhibitors of phospholipase A(2) (4-bromophenacyl-bromide), phospholipase C (neomycin) and protein kinase C (H-7) dramatically change the way the pH(i) is modulated by local cell density, It is suggested that cell-cell interactions regulate cell activities via modulation of pH(i), which is under positive control from phospholipase A2 and under negative control from protein kinase C.