Potentiation of A2 purinoceptor-stimulated surfactant phospholipid secretion in primary cultures of rat type II pneumocytes.

Surfactant secretion is mediated by a number of different signal-transduction mechanisms. Positive and negative interactions between different signaling pathways can have an important influence on the overall regulation of secretion. To examine interactions between the adenosine A2 receptor-mediated pathway and those involving activation of protein kinase C and a Ca++/calmodulin-dependent system, we examined the effect of the A2 agonist 5'-(N-ethylcarboxyamido) adenosine (NECA) in combination with 2 activators of protein kinase C, 12-O-tetradecanoylphorbol-13-acetate (TPA) and dioctanoylglycerol, and the Ca++ ionophore ionomycin on phosphatidylcholine secretion in primary cultures of rat type II cells. The individual agonists increased secretion 3-5-fold over the rate in control cells. The stimulatory effects of NECA+TPA, NECA+dioctanoylglycoerol, and NECA+ionomycin were 44%, 20%, and 44% greater, respectively, than expected by addition of the effects of the individual agonists. NECA increased cAMP formation while the other agonists did not. However, the effect of NECA on cAMP formation was significantly enhanced by TPA and dioctanoylglycerol, while the duration of the increase in cAMP level was prolonged by dioctanoylglycerol and ionomycin. Although the possible involvement of other second messenger systems cannot be excluded, we speculate that the synergistic interaction between the agonists in stimulating phosphatidylcholine secretion is mediated by increased cAMP levels.