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
Adrenaline was found to produce a much greater stimulation of adenylyl cyclase when the full population of beta 2-adrenoceptor was occupied at a low rate of receptor association compared to when a small but instantaneously equivalent number of beta 2-adrenoceptor was occupied completely. These data imply that both the frequency of beta 2-adrenoceptor occupancy and the duration of such occupancy are important determinants of adenylyl cyclase activation. Diagrammatic comparisons of the "collision coupling" models and the derived "encounter coupling" model of Stickle and Barber A 'COUN ER LI1OCCLp'I'C1 L...
This finding has subsequently been confirmed and extended to a range of other contractile agonists including histamine, cysteine-containing leukotrienes, endothelin and tachkykinins in airways smooth muscle from a range of species (although the degree and mechanism of functional antagonism varies). The degree of partial agonism assessed in functional studies of airways smooth muscle is therefore always dependent on the conditions of the assay and this is true of all species studied to date. In species such as the guinea-pig even partial agonists with relatively low intrinsic activity (clenbuterol, salmeterol) can produce a full relaxation of the tracheal smooth muscle from basal, but not induced, tone suggesting that the signal transduction system is particularly efficient.
Comparable degrees of PKA activation required an approximate 100% increase in cAMP content in the case of 36 G. P. Anderson isoprenaline whereas a 500% increase in cAMP was necessary in the case of forskolin . One interpretation of these data is that PKA (or cAMP) may be functionally compartmentalized such that cAMP generated at different location in the cell does not have the same statistical chance of diffusing to the PKA holoenzyme. This interpretation is consistent with immunocytological studies which clearly demonstrate discrete subcellular localisation patterns of cAMP and cGMP in response to different agonists .