Unique mechanisms of β-adrenoceptor sensitization and desensitization during development

Receptor desensitization is the major mode by which cells limit the degree and duration of agonist-induced stimulation. In the case of cardiac β-adrenoceptors, we have shown that this is not an inherent property of cells but rather is acquired as a distinct developmental process. In fact, stimulation of receptors in the neonatal rat leads instead to heterologous response sensitization. The current study evaluates the mechanisms underlying neonatal sensitization and the subsequent development of the ability to evoke desensitization. Animals were pretreated with isoproterenol daily for 4 days and membrane preparations were evaluated on the 5th day (6, 15, 25 days old and adults). Uniquely in the 6 day old animals, adenylyl cyclase (AC) activity was induced by isoproterenol pretreatment, resulting in heterologous sensitization, including an enhanced response to β-adrenoceptor stimulation. [3H]Forskolin binding assays indicated increases in AC catalytic units (↑Bmax) and a shift in the AC isoform being expressed (↑Kd), the same type of change seen normally between 6 and 25 days of age. In neonates, isoproterenol pretreatment also caused a decrement in the ability of Mn2+ to stimulate AC, again a characteristic of the AC isoform ordinarily seen in older animals. With the development of desensitization by day 15, isoproterenol pretreatment failed to induce AC. Instead, the ability of G-proteins to stimulate AC was impaired as evidenced by decreased response to NaF, resulting in heterologous desensitization, an event which does not occur in the neonate. These results have important implications for the regulation of adrenergic reactivity during human development in light of the surge of catecholamines that occurs during delivery and of the widespread use of β-adrenoceptor agonists in premature labor.

Duke Scholars

Author Frederic J. Seidler Pharmacology & Cancer Biology

Author Theodore Alan Slotkin Pharmacology & Cancer Biology