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J. Biol. Chem., Vol. 280, Issue 12, 11560-11568, March 25, 2005

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Distinct Conformations of the Corticotropin Releasing Factor Type 1 Receptor Adopted following Agonist and Antagonist Binding Are Differentially Regulated^*

Stephen J. Perry, Sachiko Junger, Trudy A. Kohout¶, Sam R. J. Hoare||, R. Scott Struthers¶, Dimitri E. Grigoriadis¶, and Richard A. Maki

From the Departments of Molecular Biology, ^¶Endocrinology, and ^||Pharmacology, Neurocrine Biosciences Inc., San Diego, California 92130

The corticotropin releasing factor (CRF) type 1 receptor (CRF₁) is a class B family G protein-coupled receptor that regulates the hypothalamic-pituitary-adrenal stress axis. Astressin is an amino-terminal truncated analog of CRF that retains high affinity binding to the extracellular domain of the receptor and is believed to act as a neutral competitive antagonist of receptor activation. Here we show that despite being unable to activate the CRF₁ receptor, astressin binding results in the internalization of the receptor. Furthermore, entirely different pathways of internalization of CRF₁ receptors are utilized following CRF and astressin binding. CRF causes the receptor to be phosphorylated, recruit -arrestin2, and to be internalized rapidly, likely through clathrin-coated pits. Astressin, however, fails to induce receptor phosphorylation or -arrestin2 recruitment, and internalization is slow and occurs through a pathway that is insensitive to inhibitors of clathrin-coated pits and caveolae. The fate of the internalized receptors also differs because only CRF-induced internalization results in receptor down-regulation. Furthermore, we present evidence that for astressin to induce internalization it must interact with both the extracellular amino terminus and the juxtamembrane domain of the receptor. Astressin binds with 6-fold higher affinity to full-length CRF₁ receptors than to a chimeric protein containing only the extracellular domain attached to the transmembrane domain of the activin IIB receptor, yet two 12-residue analogs of astressin have similar affinities for both proteins but are unable to induce receptor internalization. These data demonstrate that agonists and antagonists for CRF₁ receptors promote distinct conformations, which are then differentially regulated.

Received for publication, November 15, 2004 , and in revised form, January 12, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130. Tel.: 858-617-7595; Fax: 858-617-7696; E-mail: sperry{at}neurocrine.com.

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