Adenosine 3',5'-cyclic monophosphate generation inhibits inositol
1,4,5-trisphosphate binding in rabbit tracheal smooth muscle.
Schramm, Craig M., Sing T. Chuang, Michael M. Grunstein.
Pediatric Pulmonary Division, University of Connecticut Health
Center, Farmington, CT 06030 and Division of Pulmonary Medicine,
Joseph Stokes Jr. Research Institute, Children's Hospital of
Philadelphia and University of Pennsylvania School of Medicine,
Philadelphia, PA 19104
APStracts 2:0154L, 1995.
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 Ca2+-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
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.
Received 27 April 1995; accepted in final form 14 August 1995.
APS Manuscript Number L124-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 15 September 1995.