Inhibition of lung surfactant secretion from alveolar type II cells and annexin II tetramer-mediated membrane fusion by phenothiazines.
We investigated the effects of phenothiazines on lung surfactant secretion from rat alveolar epithelial type II cells and on annexin II tetramer (Anx IIt)-mediated membrane fusion. Trifluoperazine and promethazine inhibited ATP-stimulated phosphatidylcholine (PC) secretion from type II cells in a dose-dependent manner. Concentrations that cause 50% inhibition (IC50) were approximately 3 and 25 microM for trifluoperazine and promethazine, respectively. Promethazine also inhibited PC secretion of type II cells stimulated by other secretagogues, including calcium ionophore A23187, phorbol 12-myristate 13-acetate, and terbutaline that are known to stimulate PC secretion via different signal transduction pathways. Since we have recently determined that Anx IIt is involved in PC secretion of type II cells, we examined whether phenothiazines influence Anx IIt's activity. Trifluoperazine and promethazine inhibited Anx IIt's ability to aggregate phosphatidylserine (PS) liposomes, to fuse PS/phosphatidylethanolamine (PE) liposomes, and to fuse PS/PE liposomes with lamellar bodies. These results suggest a relationship between lung surfactant secretion and Anx IIt-mediated membrane fusion.
Liu
L
L
Institute for Environmental Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Tao
J Q
JQ
Li
H L
HL
Zimmerman
U J
UJ
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D017306:Annexin A2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D008081:Liposomes / Q000378:metabolism; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects*; D010640:Phenothiazines / Q000494:pharmacology*; D010713:Phosphatidylcholines / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011398:Promethazine / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013726:Terbutaline / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014268:Trifluoperazine / Q000494:pharmacology
D017306:Annexin A2; D001993:Bronchodilator Agents; D008081:Liposomes; D010640:Phenothiazines; D010713:Phosphatidylcholines; D010743:Phospholipids; D011663:Pulmonary Surfactants; D014268:Trifluoperazine; D000001:Calcimycin; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D011398:Promethazine; D013726:Terbutaline; D013755:Tetradecanoylphorbol Acetate