cAMP generation inhibits inositol 1,4,5-trisphosphate binding in rabbit tracheal smooth muscle.
Agonist-induced airway contraction involves the generation and subsequent binding of the phosphoinositide-derived second messenger, inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], to its Ca(2+)-mobilizing intracellular receptor. To the extent that regulatory cross-talk is known to exist between different signal transduction pathways, the present study examined whether activation of the adenosine 3',5'-cyclic monophosphate (cAMP)/protein kinase A (PKA) pathway induces altered binding of Ins(1,4,5)P3 to its receptor in membrane homogenates of rabbit tracheal smooth muscle (TSM). In control TSM, monophasic binding curves provided mean +/- SE values for Ins(1,4,5)P3 receptor density (Bmax) and binding affinity (Kd) amounting to 940 +/- 43 fmol/mg protein and 10.7 +/- 1.2 nM, respectively. Relative to control, binding of [3H]Ins(1,4,5)P3 was significantly reduced in paired TSM separately treated with isoproterenol, forskolin, or dibutyryl-cAMP. Ins(1,4,5)P3 binding was inhibited to a level averaging 60% of control binding by maximal concentrations of each agonist, an effect attributed to a reduction in Ins(1,4,5)P3 binding sites rather than altered ligand affinity. Collectively, these findings demonstrate that activation of the cAMP-dependent signaling pathway is associated with inhibition of Ins(1,4,5)P3 receptor binding and implicate a novel mechanism of action of beta-adrenergic agents in preventing and/or reversing airway contraction.
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009994:Osmolar Concentration; D011817:Rabbits; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
D005576:Colforsin; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D007545:Isoproterenol