REGULATION OF INTRACELLULAR PH BY CELL-CELL ADHESIVE INTERACTIONS

As was shown in our previous work, the intracellular pH (pH(i)) of cul tured human fibroblasts depends on cell density, The pH(i) is low in s ingle cells, higher in cells, forming small groups and maximal in a sp arse monolayer, On the other hand, the pH(i) is low in areas of conflu ent monolayers. In the present work, we show that the effects of inhib itors of various pH-controlling mechanisms as well as inhibitors of ke y enzymes in signal transduction pathways depend on the local cell den sity, 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; meanwhil e 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 b y intercellular contacts. Inhibitors of phospholipase A(2) (4-bromophe nacyl-bromide), phospholipase C (neomycin) and protein kinase C (H-7) dramatically change the way the pH(i) is modulated by local cell densi ty, It is suggested that cell-cell interactions regulate cell activiti es via modulation of pH(i), which is under positive control from phosp holipase A2 and under negative control from protein kinase C.