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Ontogeny of beta-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation.

Publication ,  Journal Article
Slotkin, TA; Saleh, JL; Zhang, J; Seidler, FJ
Published in: Brain Res
December 2, 1996

The ability of adrenergic stimulation to elicit desensitization of the beta-receptor/adenylyl cyclase signaling cascade is not an inherent property of cells but rather is acquired during the period in which sympathetic innervation develops. This study examines whether innervation provides the signal that enables target cardiac and hepatic cells to learn to desensitize their responses. Neonatal rats were sympathectomized with 6-OHDA on postnatal day 1 and were treated at various ages with a regimen of isoproterenol known to elicit desensitization in adults. In control rats, desensitization first appeared between days 6 and 15. Desensitization was heterologous, involving changes in the efficiency of G-protein coupling, as there were parallel decreases in isoproterenol-stimulated adenylyl cyclase activity, basal activity and fluoride-stimulated activity (maximal G-protein activation) without changes in forskolin-Mn2+-stimulated activity (total cyclase catalytic activity). The lesioned animals showed a delay in the onset of desensitization as isoproterenol did not evoke decreased responsiveness until day 25 in the heart; the liver did not display agonist-induced desensitization even at day 25. The effects of lesioning on development of desensitization were entirely separable from those on regulation of beta-receptors themselves: agonist-induced decreases in receptor binding appeared by day 15 in both control and lesioned animals. Uniquely in the youngest animals (6 days old), isoproterenol treatment produced heterologous sensitization of adenylyl cyclase responses rather than desensitization, with a parallel increase in basal, isoproterenol-, fluoride- and forskolin-Mn2+-stimulated activity; the latter indicates induction of total catalytic activity as the primary mechanism of sensitization. The lesioned neonates did not show sensitization, despite the fact that during this period, sympathetic pathways are not functionally competent. Our results indicate that innervation provides a timing signal for the onset of desensitization capabilities of sympathetic target cells, but is not absolutely required for the cells to learn how to desensitize. Prior to the onset of desensitization, agonists induce sensitization that may be important in preserving physiological responsiveness during ontogenetic surges of adrenergic activity. The absence of sensitization in lesioned animals implies that, before physiological function is completely established, early pioneer synapses provide a trophic signal that enables cells to increase their sensitivity to stimulation during the perinatal transition period.

Duke Scholars

Published In

Brain Res

DOI

ISSN

0006-8993

Publication Date

December 2, 1996

Volume

742

Issue

1-2

Start / End Page

317 / 328

Location

Netherlands

Related Subject Headings

  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pregnancy
  • Oxidopamine
  • Neurology & Neurosurgery
  • Isoproterenol
  • Heart
  • Female
  • Animals, Newborn
 

Citation

APA
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ICMJE
MLA
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Slotkin, T. A., Saleh, J. L., Zhang, J., & Seidler, F. J. (1996). Ontogeny of beta-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation. Brain Res, 742(1–2), 317–328. https://doi.org/10.1016/s0006-8993(96)00978-x
Slotkin, T. A., J. L. Saleh, J. Zhang, and F. J. Seidler. “Ontogeny of beta-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation.Brain Res 742, no. 1–2 (December 2, 1996): 317–28. https://doi.org/10.1016/s0006-8993(96)00978-x.
Slotkin TA, Saleh JL, Zhang J, Seidler FJ. Ontogeny of beta-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation. Brain Res. 1996 Dec 2;742(1–2):317–28.
Slotkin, T. A., et al. “Ontogeny of beta-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation.Brain Res, vol. 742, no. 1–2, Dec. 1996, pp. 317–28. Pubmed, doi:10.1016/s0006-8993(96)00978-x.
Slotkin TA, Saleh JL, Zhang J, Seidler FJ. Ontogeny of beta-adrenoceptor/adenylyl cyclase desensitization mechanisms: the role of neonatal innervation. Brain Res. 1996 Dec 2;742(1–2):317–328.
Journal cover image

Published In

Brain Res

DOI

ISSN

0006-8993

Publication Date

December 2, 1996

Volume

742

Issue

1-2

Start / End Page

317 / 328

Location

Netherlands

Related Subject Headings

  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pregnancy
  • Oxidopamine
  • Neurology & Neurosurgery
  • Isoproterenol
  • Heart
  • Female
  • Animals, Newborn