Hormone receptor-mediated stimulation of adenylyl cyclase systems. Nucleotide effects and analysis in terms of a simple two-state model for the basic receptor-affected enzyme

R. Iyengar, J. Abramowitz, M. Bordelon-Riser, L. Birnbaumer

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Abstract

A two-state enzyme model that appears to account for the basic guanyl nucleotide regulation of adenylyl cyclase was tested for its 'response' to 'hormone receptor-like' regulation. The effect of hormonal stimulation of the model was explored by assuming that receptors modify the inactive zero (0) state to active prime (') state isomerization reactions of both the free and the ligand-occupied enzyme. Simulations according to analytical solutions of this model, in which hormone effects a change in the isomerization reaction that is linearly dependent on receptor occupancy, showed a 'nonlinear' relationship between stimulus and response, i.e., 50% of response occurred at less than 50% change in isomerization. The more displaced isomerization was toward the active prime state; the larger was the difference between the 50% points. Thus, the model predicts hormone dose-response curves in the presence of an effective nucleotide (e.g. guanyl-5'-yl imidodiphosphate, capable on its own of stabilizing most of the enzyme in the active prime state) to be to the left of dose-response curves obtained in the presence of a less effective nucleotide (e.g. GTP or guanyl-5'-yl diphosphonate). The model also predicts that hormonal stimulation might come about even in the absence of a nucleotide or in the presence of a very ineffective nucleotide such as GDP, provided the receptor is active. Experimental data on relative positions of dose-response curves for hormones in four adenylyl cyclase systems as well as the fact that stimulation by glucagon and catecholamine was observed in the presence of saturating GDP bear out these predictions of the model. Experimental data can be accounted for by the two-state model regardless of whether adenylyl cyclase is assumed to be intimately associated with a GTPase.

Original languageEnglish
Pages (from-to)3558-3564
Number of pages7
JournalJournal of Biological Chemistry
Volume255
Issue number8
StatePublished - 1980
Externally publishedYes

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