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J. Biol. Chem., Vol. 277, Issue 24, 21379-21388, June 14, 2002
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i2,3*
From the Division of Endocrinology, Department of Internal
Medicine, University of Iowa College of Medicine and Veterans
Administration Medical Center, Iowa City, Iowa 52246
The adrenal steroid dehydroepiandrosterone (DHEA)
has no known cellular receptor or unifying mechanism of action, despite evidence suggesting beneficial vascular effects in humans. Based on
previous data from our laboratory, we hypothesized that DHEA binds to
specific cell-surface receptors to activate intracellular G-proteins
and endothelial nitric-oxide synthase (eNOS). We now pharmacologically
characterize a putative plasma membrane DHEA receptor and define its
associated G-proteins. The [3H]DHEA binding to
isolated plasma membranes from bovine aortic endothelial cells was of
high affinity (Kd = 48.7 pM) and
saturable (Bmax = 500 fmol/mg protein).
Structurally related steroids failed to compete with DHEA for binding.
The putative DHEA receptor was functionally coupled to G-proteins,
because guanosine 5'-O-(3-thio)triphosphate (GTP
S)
inhibited [3H]DHEA binding to plasma membranes by 69%,
and DHEA increased [35S]GTPS binding by 157%. DHEA
stimulated [35S]GTPS binding to G
i2 and
Gi3, but not to Gi1 or Go.
Pretreatment of plasma membranes with antibody to Gi2 or
Gi3, but not to Gi1, inhibited the DHEA
activation of eNOS. Thus, DHEA receptors are expressed on endothelial
cell plasma membranes and are coupled to eNOS activity through
Gi2 and Gi3. These novel findings should allow us to isolate the putative receptor and reevaluate the
physiological role of DHEA activity.
To whom correspondence should be addressed: VA Medical Center,
3E10, Iowa City, IA 52246. Tel.: 319-338-0581 (ext. 7640); Fax:
319-339-7025; E-mail: joseph-dillon@uiowa.edu.
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