PKC role in mechanically induced Ca2+ waves and ATP-induced Ca2+ oscillations in airway epithelial cells

Mechanical stimulation of airway epithelial cells generates the Ca2+ mobili zation messenger inositol 1,4,5-trisphosphate and the protein kinase (PK)C activator diacylglycerol. Inositol 1,4,5-trisphosphate diffuses through gap junctions to mediate intercellular communication of the mechanical stimulu s (a "Ca2+ wave"); the role that diacylglycerol-activated PKC might play in the response is unknown. Using primary cultures of rabbit tracheal cells, we show that 12-O-tetradecanoylphorbol 13-acetate- or 1,2-dioctanyl-sn-glyc erol-induced activation of PKC slows the Ca2+ wave, decreases the amplitude of induced intracellular free Ca2+ concentration ([Ca2+](i)) increases, an d decreases the number of affected cells. The PKC inhibitors bisindolylmale imide and Go 6976 slowed the spread of the wave but did not change the numb er of affected cells. We show that ATP-induced [Ca2+](i) increases and osci llations, responses independent of intercellular communication, were inhibi ted by PKC activators. Bisindolylmaleimide decreased the amplitude of ATP-i nduced [Ca2(+)](i) increases and blocked oscillations, suggesting that PKC has an initial positive effect on Ca2+ mobilization and then mediates feedb ack inhibition. PKC activators also reduced the [Ca2+](i) increase that fol lowed thapsigargin treatment, indicating a PKC effect associated with the C a2+ release mechanism.