Alpha2-adrenergic receptor-mediated regulation of adenylate cyclase in the intact human platelet. Evidence for a receptor reserve

R. H. Lenox, John Ellis, D. Van Riper, Y. H. Ehrlich

Research output: Contribution to journalArticle

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Abstract

The alpha2-adrenergic receptor on the human platelet is known to mediate the inhibition of adenylate cyclase activity. A comparison of the binding and response properties of intact cells revealed that the full agonists norepinephrine and epinephrine inhibit cyclic AMP accumulation with apparently higher affinity than they exhibit in inhibiting the binding of [3H]yohimbine. Additionally, Hill coefficients of the occupancy curves of the agonists were less than unity, suggesting the presence of a heterogeneous receptor population in intact platelets under conditions that permit robust inhibition of cyclic AMP accumulation. The partial agonist clonidine was found to possess the same affinity in the binding assay as in the response assay. These data are consistent with the presence of a receptor reserve in this system, a suggestion that was confirmed in experiments utilizing the irreversible alpha2 antagonist phenoxybenzamine. The IC50 (100 nM) derived from the blockade of [3H]yohimbine binding by phenoxybenzamine was significantly less than the IC50 (550 nM) for the corresponding reversal by phenoxybenzamine of the effects of norepinephrine on cyclic AMP accumulation. Further studies demonstrated a rightward shift in the dose-response curves for the inhibition by norepinephrine of cyclic AMP accumulation following pretreatment with increasing phenoxybenzamine concentration. These data consistently indicated that occupancy of approximately 10% of the alpha2-adrenergic receptors by norepinephrine elicits a half-maximal adenylate cyclase response. The relationship of these findings to current models of receptor-effector coupling is discussed.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalMolecular Pharmacology
Volume27
Issue number1
StatePublished - 1985

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Phenoxybenzamine
Adenylyl Cyclases
Cyclic AMP
Adrenergic Receptors
Norepinephrine
Blood Platelets
Yohimbine
Inhibitory Concentration 50
Clonidine
Epinephrine
Population

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "Alpha2-adrenergic receptor-mediated regulation of adenylate cyclase in the intact human platelet. Evidence for a receptor reserve",
abstract = "The alpha2-adrenergic receptor on the human platelet is known to mediate the inhibition of adenylate cyclase activity. A comparison of the binding and response properties of intact cells revealed that the full agonists norepinephrine and epinephrine inhibit cyclic AMP accumulation with apparently higher affinity than they exhibit in inhibiting the binding of [3H]yohimbine. Additionally, Hill coefficients of the occupancy curves of the agonists were less than unity, suggesting the presence of a heterogeneous receptor population in intact platelets under conditions that permit robust inhibition of cyclic AMP accumulation. The partial agonist clonidine was found to possess the same affinity in the binding assay as in the response assay. These data are consistent with the presence of a receptor reserve in this system, a suggestion that was confirmed in experiments utilizing the irreversible alpha2 antagonist phenoxybenzamine. The IC50 (100 nM) derived from the blockade of [3H]yohimbine binding by phenoxybenzamine was significantly less than the IC50 (550 nM) for the corresponding reversal by phenoxybenzamine of the effects of norepinephrine on cyclic AMP accumulation. Further studies demonstrated a rightward shift in the dose-response curves for the inhibition by norepinephrine of cyclic AMP accumulation following pretreatment with increasing phenoxybenzamine concentration. These data consistently indicated that occupancy of approximately 10{\%} of the alpha2-adrenergic receptors by norepinephrine elicits a half-maximal adenylate cyclase response. The relationship of these findings to current models of receptor-effector coupling is discussed.",
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Alpha2-adrenergic receptor-mediated regulation of adenylate cyclase in the intact human platelet. Evidence for a receptor reserve. / Lenox, R. H.; Ellis, John; Van Riper, D.; Ehrlich, Y. H.

In: Molecular Pharmacology, Vol. 27, No. 1, 1985, p. 1-9.

Research output: Contribution to journalArticle

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