Neural input and the development of adrenergic intracellular signaling: neonatal denervation evokes neither receptor upregulation nor persistent supersensitivity of adenylate cyclase.
In the adult, denervation of adrenergic target tissues leads to compensatory upregulation of receptor sites and to supersensitive responses. When 6-hydroxydopamine (6-OHDA) was given to neonatal rats, cardiac beta-receptors failed to show significant upregulation throughout the first five postnatal weeks and alpha 1-receptors were unchanged except at 35 days of age, despite 70-95% depletion of norepinephrine. The failure to upregulate could not be attributed to the high background level of receptor expression commensurate with ontogenetic increases in receptor numbers, since the same deficiency was seen in the liver, a tissue in which beta-receptors decline with development; liver alpha 1-receptors also failed to upregulate after neonatal denervation. Examination of the linkage of beta-receptors to adenylate cyclase indicated major differences from mature regulatory mechanisms, as denervation supersensitivity was completely absent (liver) or emerged only transiently several weeks after 6-OHDA treatment (heart). In the heart, there was evidence for a defect in the G-protein-dependent component of the receptor/cyclase linkage that could contribute to the delayed appearance of supersensitivity. Because the fundamental patterns of receptor ontogeny and of adenylate cyclase responsiveness are still present after neonatal denervation, it is unlikely that neural input provides the major impetus for basal development. However, adult-type regulation of receptors and responses did not emerge even after a prolonged period; thus, neural input during a critical developmental stage may be required for the cell to learn how to adjust receptor expression and the receptor/cyclase link in response to stimulation.
Slotkin, TA; Lorber, BA; McCook, EC; Barnes, GA; Seidler, FJ
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