By Gary P. Anderson (auth.), Dr. David Raeburn, Dr. Mark A. Giembycz (eds.)
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Extra info for Airways Smooth Muscle: Neurotransmitters, Amines, Lipid Mediators and Signal Transduction
E. beta 2-adrenoceptor antagonists that have a higher affinity for low affinity state of the beta 2-adrenoceptors and which inhibit the slight basal activity of the beta 2-adrenoceptors population . Indirect evidence for an inactive: active equilibrium comes from transfection experiments where very high copy numbers of G protein coupled NPY receptors are expressed leading to signal transduction in the absence of agonist. In addition, indirect evidence for a dynamic equilibrium between high and low affinity state beta 2-adrenoceptors comes from the observation that leI 118,551, a highly selective beta 2-adrenoceptor antagonist behaves as a "negative antagonist" causing a reduction in basal cAMP turnover in the absence of exogenous agonist.
The ex subunit has a high affinity guanine nucleotide binding site, possesses intrinsic GTPase activity and binds Mg2+. Guinea-pig trachea contains both Giex and Gsex as assessed by western blotting of membrane extracts with specific antibodies . Reconstitution experiments support the concept that GTP activated Gsex stimulates the activity of adenylyl cyclase leading to formation of cyclic AMP . A measure of debate surrounds the exact molecular mechanism by which the association of Gs with the beta 2-adrenoceptor (or beta l-adrenoceptor) leads to signal transduction via adenylyl cyclase .
The dynamics of cAMP accumulation in response to adrenoceptor activation has been well studied in intact airways smooth muscle and in isolated dispersed airways smooth muscle cells in vitro [34, 172, 173]. mg protein -I in the presence of supramaximal concentrations (100 IlM) of GTP and isoprenaline . This study is notable because the authors measured the actual rate of cAMP formation rather than cAMP content. The distinction is important because rate of formation of cAMP is probably more important than the total content of cAMP measured in relation to airways smooth muscle relaxation.