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Vol. 286, Issue 1, 459-468, July 1998
CNS Diseases Research, The DuPont Merck Research Laboratories,
Wilmington Delaware
We describe the binding of
[125I]tyrosauvagine to membranes of
corticotropin-releasing hormone (CRH2) receptor expressing
HEK293/EBNA (293ECRH2) cells. The binding of
[125I]tyrosauvagine to CRH2
receptors was temperature, time and tissue dependent. Equilibrium was
reached in 2 hr at 23°C. Saturation data best fit a two-site model
with affinity constants of 44 pM and 4.1 nM for high and low affinity
states, respectively. The high affinity [125I]tyrosauvagine binding sites were
eliminated with 200 µM Gpp (NH) p, indicating coupling to G proteins.
The rank order potency of peptide analogs of CRH to inhibit
[125I]tyrosauvagine binding to
CRH2 receptors was: urotensin > sauvagine = urocortin > 
-helical CRH9-41 > rh-CRH
o-CRH. This was in contrast to the rank order potency of
the peptides at inhibiting [125I]tyrooCRH
binding to CRH1 receptors: urotensin > urocortin > r/h-CRH> o-CRH = sauvagine > -helical
CRH9-41. We show that two recently identified small
molecule CRH antagonists with nanomolar potency at the CRH1
receptor, have little or no affinity for
CRH2 receptors as labeled by
[125I]tyrosauvagine. Two selective
CRH1 receptor antagonists enabled us to examine comparative
densities of CRH1 and CRH2 receptors in several
brain areas. We also used [125I]tyrosauvagine
in combination with a specific CRH1 antagonist to examine the anatomic distribution of CRH2 receptors using receptor
autoradiography. With a few notable exceptions the CRH2
receptors demonstrated autoradiographically in this study match the
data obtained by in situ hybridization studies on the
localization of CRH2 mRNA. The anatomic overlap of the
autoradiographic and in situ hybridization data suggest
that CRH2 receptors are postsynaptic. This study demonstrates the utility of using
[125I]tyrosauvagine to study cloned
CRH2 receptors expressed in cell lines. In addition,
[125I]tyrosauvagine used in conjunction with
saturating concentrations of a specific CRH1 receptor
antagonist allows the study of CRH2 receptors in brain
tissues using both in vitro homogenate binding and
receptor autoradiography techniques.
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