Agonist-related differences in the relationship between cAMP content and protein kinase activity in canine trachealis.
We investigated the relationships between relaxation, cyclic AMP (cAMP) accumulation and cAMP-dependent protein kinase (cAMP-PK) activity in canine tracheal smooth muscle. In time course and concentration-response studies, forskolin and isoproterenol elicited relaxation of isolated trachealis strips that was accompanied by an increase in cAMP content and an activation of cAMP-PK. Although these results were consistent with the proposal that cAMP is a second messenger mediating relaxation of airway smooth muscle, close inspection of the data revealed a discrepancy in the relationship between cAMP accumulation and relaxation. To induce equivalent degrees of tracheal relaxation, forskolin generated greater increments in cAMP accumulation than did isoproterenol. On the other hand, the activation state of cAMP-PK correlated reasonably well with relaxation regardless of which agonist was used. Further analysis of the data revealed that the apparent disparity between cAMP accumulation and relaxation could largely be explained at the level of the relationship between cAMP content and cAMP-PK activity: compared to isoproterenol, forskolin induced greater increases in cAMP accumulation to achieve the same activation state of cAMP-PK. These observations lend support to the proposal that in canine trachealis, various components of the cAMP/cAMP-PK cascade exist in distinct subcellular compartments such that not all of the cAMP generated in response to forskolin has access to its target enzyme, cAMP-PK.
Zhou
H L
HL
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Newsholme
S J
SJ
Torphy
T J
TJ
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D005576:Colforsin; D000242:Cyclic AMP; D011494:Protein Kinases; D007545:Isoproterenol