β-Adrenoreceptors determine affinity but not intrinsic activity of adenylate cyclase stimulants

Abstract

SIGNIFICANT progress has recently been made toward defining and understanding the molecular basis of hormone sensitivity in the β-adrenoreceptor-adenylate cyclase system. Through the use of biochemical^1,2 and genetic^3,4 techniques it has become apparent that this system is comprised of at least three separate components: the β-adrenoreceptor, which is responsible for the binding of β-adrenergic agents; the catalytic unit of the enzyme adenylate cyclase, responsible for the conversion of ATP to cyclic AMP; and a nucleotide regulatory component or components which seems to possess a GTPase activity⁵ and to be required for coupling of the β-adrenoreceptor to the adenylate cyclase enzyme⁶. As has been demonstrated by Orly and Schramm⁷ and confirmed by Schwarzmeier and Oilman⁸ in cell fusion experiments, these components interact to produce the hormone-responsive adenylate cyclase system and this interaction occurs even when the separate functions are donated by heterologous cell types. Frog and turkey erythrocytes each possess a catecholamine-responsive adenylate cyclase. Although similar in some respects these two well-studied systems differ markedly with respect to their drug affinities and intrinsic activities. Intrinsic activity is defined as the maximal ability of a drug to stimulate a biological or biochemical response. To elucidate the role of the β-adrenoreceptor in the expression of these properties, we report here the use of cell fusion techniques to construct a hybrid which possesses the β-adrenoreceptor of the turkey erythrocyte and the adenylate cyclase of the frog erythrocyte. The characteristics of this hybrid indicate that although the receptor determines relative drug affinities (for example, β₁ compared with β₂ subtypes of receptor), it is a component distal to the receptor which determines relative drug intrinsic activities.