Role of Protein Kinases in the Desensitization-Sensitization of β-Adrenergic Receptor and Prostaglandin Receptor Stimulation of Adenylyl Cyclase

Abstract

Desensitization of hormonal stimulation of adenylyl cyclase in the S49 wild type (WT) lymphoma cells is complex. At least five types of desensitization of the β-adrenergic receptor response have been identified (fig 1) at the receptor level. These include: (1) cAMPdependent protein kinase (cA•PK)-mediated heterologous desensitization of hormonal stimulation which occurs rapidly in response to low concentrations (EC₅₀ of about 10 nM) of either epinephrine or PGE₁, or any drug which increases cAMP (Clark et al. 1988); (2) homologous desensitization associated with the sequestration and internalization of the β-adrenergic receptor which occurs rapidly in response to high concentrations of epinephrine (EC₅₀ about 200 nM), is dependent on substantial agonist occupation of the receptor, and is independent of G_s, cAMP or cA•PK (Green et al. 1981, Clark et al. 1985) and has been suggested to involve multiple phosphorylations by β-adrenergic receptor kinase (Benovic et al. 1987); (3) a protein kinase C (PKC)-mediated heterologous desensitization which occurs in response to relatively high concentrations of the phorbol ester PMA with an EC₅₀ of about 100 nM (Johnson et al. 1986); (4) a slow homologous down regulation of the β-adrenergic receptor, characterized by the loss of antagonist binding, which proceeds with a half-life of about 2 hr in the WT and 6 hr in the cyc mutant (Clark et al. 1985); and (5) a slow homologous desensitization of the β-adrenergic receptor which occurs in response to treatment of cells with low concentrations of epinephrine (3–5 nM) for prolonged periods of time (half-life about 2–4 hr) and which may be, in part, mediated by cA•PK (Butcher et al. 1987).