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Receptor crosstalk: effects of prolonged carbachol exposure on beta 1-adrenoceptors and adenylyl cyclase activity in neonatal rat ventricular myocytes.

Publication ,  Journal Article
Paraschos, A; Karliner, JS
Published in: Naunyn Schmiedebergs Arch Pharmacol
September 1994

Supersensitivity of adenylyl cyclase after exposure to inhibitory agonists is a general means of cellular adaptation. We hypothesized that such "crosstalk" between muscarinic cholinergic agonists, beta 1-adrenoceptors, and adenylyl cyclase may be an important mechanism of cardiac adaptation to interventions that enhance vagal activity. We used primary cultures of neonatal rat ventricular myocytes and measured beta-adrenoceptors by radioligand binding and adenylyl cyclase activity by a single column method. Carbachol induced a time- and dose-dependent reversible decrease in cell surface beta 1-adrenoceptors. The peak effect occurred after 20 h of exposure to 100 microM carbachol which caused a decrease in the maximum number of binding sites for the beta-adrenoceptor antagonist 3H-CGP-12177 from 42.3 +/- 3.4 to 33.0 +/- 2.6 fmol/mg protein (n = 12, P < 0.03) without a change in antagonist affinity. Loss of cell surface receptors was prevented by atropine and by the protein kinase C inhibitor H7. The decrease in cell surface receptors was not accompanied by receptor internalization as assessed by equilibrium binding experiments in a cytosolic fraction using 125I-iodocyanopindolol. In contrast to the well-known acute inhibitory effects of carbachol on adenylyl cyclase activation, prolonged carbachol exposure preserved (-)-isoprenaline-stimulated adenylyl cyclase activity and enhanced postreceptor stimulated adenylyl cyclase activity. Carbachol did not further enhance adenylyl cyclase activity after pretreatment with pertussis toxin. The protein kinase C inhibitor chelerythrine prevented the carbachol induced enhancement of forskolin-stimulated adenylyl cyclase activity. We conclude that prolonged incubation with carbachol in rat neonatal ventricular myocytes causes a reduction in cell surface beta 1-Adrenoceptor density. beta 1-Adrenoceptor-mediated adenylyl cyclase activity is preserved and postreceptor-mediated adenylyl cyclase activity is augmented. Our data suggest that carbachol-stimulated protein kinase C activity may play a key role in the prolonged muscarinic regulation of adenylyl cyclase activity.

Duke Scholars

Published In

Naunyn Schmiedebergs Arch Pharmacol

DOI

ISSN

0028-1298

Publication Date

September 1994

Volume

350

Issue

3

Start / End Page

267 / 276

Location

Germany

Related Subject Headings

  • Tritium
  • Time Factors
  • Signal Transduction
  • Receptors, Muscarinic
  • Receptors, Adrenergic, beta-1
  • Rats
  • Protein Kinase C
  • Propanolamines
  • Pharmacology & Pharmacy
  • Myocardium
 

Citation

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Paraschos, A., & Karliner, J. S. (1994). Receptor crosstalk: effects of prolonged carbachol exposure on beta 1-adrenoceptors and adenylyl cyclase activity in neonatal rat ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol, 350(3), 267–276. https://doi.org/10.1007/BF00175032
Paraschos, A., and J. S. Karliner. “Receptor crosstalk: effects of prolonged carbachol exposure on beta 1-adrenoceptors and adenylyl cyclase activity in neonatal rat ventricular myocytes.Naunyn Schmiedebergs Arch Pharmacol 350, no. 3 (September 1994): 267–76. https://doi.org/10.1007/BF00175032.
Paraschos, A., and J. S. Karliner. “Receptor crosstalk: effects of prolonged carbachol exposure on beta 1-adrenoceptors and adenylyl cyclase activity in neonatal rat ventricular myocytes.Naunyn Schmiedebergs Arch Pharmacol, vol. 350, no. 3, Sept. 1994, pp. 267–76. Pubmed, doi:10.1007/BF00175032.
Journal cover image

Published In

Naunyn Schmiedebergs Arch Pharmacol

DOI

ISSN

0028-1298

Publication Date

September 1994

Volume

350

Issue

3

Start / End Page

267 / 276

Location

Germany

Related Subject Headings

  • Tritium
  • Time Factors
  • Signal Transduction
  • Receptors, Muscarinic
  • Receptors, Adrenergic, beta-1
  • Rats
  • Protein Kinase C
  • Propanolamines
  • Pharmacology & Pharmacy
  • Myocardium