Seven Helix Receptors are Enzymes Catalysing G Protein Activation. What is the Agonist Kact?

We analysed a model assuming that the G protein activation process is an enzyme catalysed reaction: (i) GGDPrecognition, (ii) GDP release, (iii) GTP binding and (iv) activated GGTP(or βγ followed by αGTP) release. This model suggests (1) that the agonists Kactvalue may decrease with increasing G protein expression. At low G protein concentrations, the agonists Kactvalue reflects binding to the ‘low affinity state’. If the G protein concentration is saturating, the agonists Kactvalues are correlated but not identical to their KDvalues for the ‘high affinity state’ observed in binding studies. (2) All the G proteins recognized by a receptor behave as competitive antagonists with respect to each other. (3) Overexpression of G proteins which recognize only the active receptor state may result in constitutive receptor activation. The rate of G protein activation can be accelerated by facilitating G protein recognition, by increasing the rate of GDP release, or by activating G protein release. Our model explains why guanyl nucleotides are essential for G proteins activation yet inhibit agonist binding, and why the ability of receptor ligands to simulate G protein activation is not always correlated with their ability to distinguish two receptor states, at equilibrium. It can also explain the inhibitory effects of GDP and of the G protein βγ subunit.