Alpha-2 adrenergic receptors mediate several important functions of the endogenous catecholamines in both the central and peripheral nervous systems. Several clinically important drugs appear to produce their pharmacologic effects through an interaction at alpha-2 receptors. There now exists considerable evidence indicating significant differences in the pharmacological characteristics and regulation of mammalian alpha-2 adrenergic receptors from various tissues and species. We suggest that differences in the pharmacological properties and in the regulation (mechanism of action) of alpha-2 adrenergic receptors may be due to differences in the structure of the alpha-2 adrenergic receptor complex. To test this hypothesis, it is proposed to compare in various tissues and species: (1) The rank order and relative potencies of various adrenergic drugs using both radioligand binding and functional assays; (2) The thermal stability and pH optima of radioligand binding; (3) The functional size of the receptor complex using target analysis (radiation inactivation); (4) The apparent molecular size determined by gel filtration and sucrose density gradient centrifugation of receptor preparations solubilized in the presence and absence of agonist; and (5) The apparent molecular weight from SDS gel electrophoresis of partially purified receptors labeled with a photoaffinity probe. These studies should help to resolve the present confusion in classification of alpha receptors and may lead to more selective alpha adrenergic drugs for clinical use.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040784-06
Application #
3298703
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1989-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
O'Rourke, M F; Iversen, L J; Lomasney, J W et al. (1994) Species orthologs of the alpha-2A adrenergic receptor: the pharmacological properties of the bovine and rat receptors differ from the human and porcine receptors. J Pharmacol Exp Ther 271:735-40
O'Rourke, M F; Blaxall, H S; Iversen, L J et al. (1994) Characterization of [3H]RX821002 binding to alpha-2 adrenergic receptor subtypes. J Pharmacol Exp Ther 268:1362-7
Blaxall, H S; Cerutis, D R; Hass, N A et al. (1994) Cloning and expression of the alpha 2C-adrenergic receptor from the OK cell line. Mol Pharmacol 45:176-81
Pleus, R C; Shreve, P E; Toews, M L et al. (1993) Down-regulation of alpha 2-adrenoceptor subtypes. Eur J Pharmacol 244:181-5
Alburges, M E; Bylund, D B; Pundt, L L et al. (1993) Alpha 2-agonist binding sites in brain: [125I]para-iodoclonidine versus [3H]para-aminoclonidine. Brain Res Bull 32:97-102
Blaxall, H S; Heck, D A; Bylund, D B (1993) Molecular determinants of the alpha-2D adrenergic receptor subtype. Life Sci 53:PL255-9
Lawhead, R G; Blaxall, H S; Bylund, D B (1992) Alpha-2A is the predominant alpha-2 adrenergic receptor subtype in human spinal cord. Anesthesiology 77:983-91
Wamsley, J K; Alburges, M E; Hunt, M A et al. (1992) Differential localization of alpha 2-adrenergic receptor subtypes in brain. Pharmacol Biochem Behav 41:267-73
Bylund, D B (1992) Subtypes of alpha 1- and alpha 2-adrenergic receptors. FASEB J 6:832-9
Bylund, D B; Blaxall, H S; Iversen, L J et al. (1992) Pharmacological characteristics of alpha 2-adrenergic receptors: comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning. Mol Pharmacol 42:1-5

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