β-Adrenergic Receptors in Pediatric Tumors: Uncoupled β1-Adrenergic Receptor in Ewing's Sarcoma

Jeffrey A. Whitsett, Jeffrey Burdsall, Linda Workman, Bryan Hollinger, John Neely

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

β-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to thCJse from 46 other pediatric cancers with the use of the β-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol mg-' protein; dissociation constant Kd, 1–2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer β-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of β,-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of β-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from competition experiments with (-)isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to Nethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in β-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with β-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.

Original languageEnglish (US)
Pages (from-to)779-786
Number of pages8
JournalJournal of the National Cancer Institute
Volume71
Issue number4
DOIs
StatePublished - Oct 1983

Fingerprint

Ewing's Sarcoma
Adrenergic Receptors
Pediatrics
Isoproterenol
Neoplasms
Adenylyl Cyclases
Guanosine Triphosphate
Adrenergic Agents
Catecholamines
Lymphoma
Dihydroalprenolol
Endodermal Sinus Tumor
Hepatoblastoma
Metoprolol
Adrenergic Antagonists
Guanine Nucleotides
Wilms Tumor
Rhabdomyosarcoma
Osteosarcoma
Neuroblastoma

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Whitsett, Jeffrey A. ; Burdsall, Jeffrey ; Workman, Linda ; Hollinger, Bryan ; Neely, John. / β-Adrenergic Receptors in Pediatric Tumors : Uncoupled β1-Adrenergic Receptor in Ewing's Sarcoma. In: Journal of the National Cancer Institute. 1983 ; Vol. 71, No. 4. pp. 779-786.
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abstract = "β-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to thCJse from 46 other pediatric cancers with the use of the β-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol mg-' protein; dissociation constant Kd, 1–2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer β-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of β,-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of β-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from competition experiments with (-)isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to Nethylmaleimide denaturation and were densensitized only 50{\%} during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in β-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with β-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.",
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β-Adrenergic Receptors in Pediatric Tumors : Uncoupled β1-Adrenergic Receptor in Ewing's Sarcoma. / Whitsett, Jeffrey A.; Burdsall, Jeffrey; Workman, Linda; Hollinger, Bryan; Neely, John.

In: Journal of the National Cancer Institute, Vol. 71, No. 4, 10.1983, p. 779-786.

Research output: Contribution to journalArticle

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T1 - β-Adrenergic Receptors in Pediatric Tumors

T2 - Uncoupled β1-Adrenergic Receptor in Ewing's Sarcoma

AU - Whitsett, Jeffrey A.

AU - Burdsall, Jeffrey

AU - Workman, Linda

AU - Hollinger, Bryan

AU - Neely, John

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N2 - β-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to thCJse from 46 other pediatric cancers with the use of the β-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol mg-' protein; dissociation constant Kd, 1–2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer β-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of β,-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of β-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from competition experiments with (-)isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to Nethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in β-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with β-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.

AB - β-Adrenergic receptors were demonstrated in membrane preparations from 6 human Ewing's sarcomas and compared to thCJse from 46 other pediatric cancers with the use of the β-adrenergic antagonist (-)-[3H]dihydroalprenolol [(-)-[3H]DHA]. In contrast to the high numbers of receptor sites found in Ewing's sarcomas (55-640 fmol mg-' protein; dissociation constant Kd, 1–2 nM), other childhood cancers (neuroblastoma, rhabdomyosarcoma, brain tumors, lymphoma, osteosarcoma, hepatoblastoma, yolk sac, and Wilms' tumor) contained in general fewer β-adrenergic receptor sites. Characteristics of (-)-[3H]DHA binding were therefore more fully characterized in the Ewing's tumors. Competition of (-)-[3H]DHA binding by classical catecholamine agonists, as well as by subtype selective agents metoprolol and zinterol, demonstrated the presence of a homogeneous population of β,-adrenergic sites in several Ewing's tumors. Adenylate cyclase activity in all Ewing's sarcomas was enhanced by GTP and NaF. However, in spite of high numbers of β-adrenergic receptors, (-)-isoproterenol was not very effective in the activation of adenylate cyclase activity in several of the Ewing's tumors tested. Neither guanyl-5'-yl-imidophosphate nor GTP altered agonist potency for the receptor site in these catecholamine-insensitive tumors. Hill coefficients obtained from competition experiments with (-)isoproterenol (in the presence or absence of guanine nucleotide) were approximately 1.0. These uncoupled receptors were resistant to Nethylmaleimide denaturation and were densensitized only 50% during culture in the presence of (-)-isoproterenol. Thus Ewing's sarcomas are relatively rich in β-adrenergic sites, and several tumors appear to have a coupling lesion involving guanine nucleotide-dependent regulatory protein interaction with β-adrenergic receptors and adenylate cyclase, similar in phenotype to that described in the (unc) variant of S49 mouse lymphoma.

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