Classical second messengers are not involved in proteinase-induced degranulation of airway gland cells.
Neutral serine proteinases such as mast cell chymase, cathepsin G, and neutrophil elastase are far more potent secretagogues for airway gland serous cells than all other agonists studied (e.g., histamine and bradykinin). To determine the mechanism of proteinase-induced secretion, we investigated the stimulation-secretion coupling in cultured bovine serous cells. Histamine stimulates degranulation of serous cells via adenosine 3', 5'-cyclic monophosphate-, protein kinase C-, and intracellular Ca2+ concentration ([Ca2+]i)-dependent pathways. Similarly, bradykinin-induced secretion involves inositol phosphates, protein kinase C, and [Ca2+]i. Degranulation caused by both agonists also depends on the activity of an endogenous metalloprotease, which is required in a late step of stimulation-secretion coupling, i.e., after Ca2+ entry. On the basis of the effect of different inhibitors, this metalloprotease is a Zn(2+)- and Ca(2+)-dependent enzyme similar to a gelatinase A synthesized by serous cells. In marked contrast to other secretagogues, degranulation induced by chymase, cathepsin G, and neutrophil elastase neither involves the classical second messengers nor the activity of the endogenous metalloprotease. These observations suggest that exogenous proteinases such as chymase, cathepsin G, and elastase may substitute for or mimic the action of an endogenous metalloprotease and directly activate degranulation, bypassing the signal transduction mechanisms necessary for secretion caused by other agonists.
Sommerhoff
C P
CP
Cardiovascular Research Institute, University of California San Francisco 94143, USA. sommerhoff@clinbio.med.uni-muenchen.de
Fang
K C
KC
Nadel
J A
JA
Caughey
G H
GH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002403:Cathepsins / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D053818:Chymases; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D012697:Serine Endopeptidases / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D015124:8-Bromo Cyclic Adenosine Monophosphate; D000001:Calcimycin; D006632:Histamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002403:Cathepsins; D012697:Serine Endopeptidases; D019272:Leukocyte Elastase; D053818:Chymases; D013755:Tetradecanoylphorbol Acetate; D001920:Bradykinin; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine