Norepinephrine-induced alteration in the coupling of. cap alpha. /sub 1/-adrenergic receptor occupancy to calcium efflux in rabbit aortic smooth muscle cells
To determine whether ..cap alpha..-adrenergic desensitization of vascular smooth muscle is due to an alteration in ..cap alpha../sub 1/-adrenergic receptor coupling, the authors determined the relationship between receptor occupancy and maximal receptor-coupled Ca/sup 2 +/ efflux in cultured rabbit aortic smooth muscle cells (i) under basal conditions as defined by receptor inactivation with phenoxybenzamine and (ii) after 48 hr of exposure to several concentrations of 1-norepinephrine (NE). Neither phenoxybenzamine nor NE exposure caused a change in binding affinity for (/sup 3/H)prazosin or NE. Maximal (/sup 3/H)prazosin binding capacity and maximal NE-stimulated /sup 45/Ca/sup 2 +/ efflux decreased progressively with exposure of incubated cells to increasing concentrations of phenoxybenzamine or NE. An approximately 80% decrease in maximal (/sup 3/H)prazosin binding capacity caused by either phenoxybenzamine or NE resulted in complete loss of NE-stimulated /sup 45/Ca/sup 2 +/ efflux, indicating that under these conditions approximately 20% of ..cap alpha../sub 1/-adrenergic receptors are not coupled to the Ca/sup 2 +/ efflux. Under basal conditions, the relationship between maximal (/sup 3/H)prazosin binding capacity and maximal NE-stimulated /sup 45/Ca/sup 2 +/ efflux was markedly nonlinear, so that a near maximal response could be elicited by occupancy of only approximately 40% of the receptors. Thus, an alteration in occupancy-response coupling at a step proximal to Ca/sup 2 +/ mobilization and/or influx, rather than a reduction in receptor number, is of primary importance in the process of agonist-induced ..cap alpha..-adrenergic receptor desensitization of vascular smooth muscle cells.
- Research Organization:
- Harvard Medical School, Boston, MA (United States)
- OSTI ID:
- 5766756
- Journal Information:
- Proc. Natl. Acad. Sci. U.S.A.; (United States), Vol. 83:6
- Country of Publication:
- United States
- Language:
- English
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