{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:54:42Z","timestamp":1783569282639,"version":"3.55.0"},"reference-count":26,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The type 1 CRH receptor (CRH-R1) plays a fundamental role in homeostatic adaptation to stressful stimuli. CRH-R1 gene activity is regulated through alternative splicing and generation of various CRH-R1 mRNA variants. One such variant is the CRH-R1d, which has 14 amino acids missing from the putative seventh transmembrane domain due to exon 13 deletion, a splicing event common to other members of the B1 family of G protein-coupled receptors. In this study, using overexpression of recombinant receptors in human embryonic kidney 293 and myometrial cells, we showed by confocal microscopy that in contrast to CRH-R1\u03b1, the R1d variant is primarily retained in the cytoplasm, although some cell membrane expression is also evident. Use of antibodies against the CRH-R1 C terminus in nonpermeabilized cells showed that membrane-expressed CRH-R1d contains an extracellular C terminus. Interestingly, treatment of CRH-R1d-expressing cells with CRH (100 nM) for 45\u201360 min elicited functional responses associated with a significant reduction of plasma membrane receptor expression, redistribution of intracellular receptors, and increased receptor degradation. Site-directed mutagenesis studies identified the cassette G356-F358 within transmembrane domain 7 as crucial for CRH-R1\u03b1 stability to the plasma membrane because deletion of this cassette caused substantial intracellular localization of CRH-R1 \u03b1. Most importantly, coexpression studies between CRH-R1d and CRH-R2\u03b2 demonstrated that the CRH-R2\u03b2 could partially rescue CRH-R1d membrane expression, and this was associated with a significant attenuation of urocotrin II-induced cAMP production and ERK1\/2 and p38MAPK activation, suggesting that CRH-R1d might specifically induce heterologous impairment of CRH-R2 signaling responses. This mechanism appears to involve accelerated CRH-R2\u03b2 endocytosis.<\/jats:p>","DOI":"10.1210\/me.2008-0177","type":"journal-article","created":{"date-parts":[[2008,9,5]],"date-time":"2008-09-05T00:49:43Z","timestamp":1220575783000},"page":"2505-2519","source":"Crossref","is-referenced-by-count":20,"title":["Structural Determinants Critical for Localization and Signaling within the Seventh Transmembrane Domain of the Type 1 Corticotropin Releasing Hormone Receptor: Lessons from the Receptor Variant R1d"],"prefix":"10.1210","volume":"22","author":[{"given":"Danijela","family":"Markovic","sequence":"first","affiliation":[{"name":"Endocrinology and Metabolism (D.M., H.L., D.K.G.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Lehnert","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism (D.M., H.L., D.K.G.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Levine","sequence":"additional","affiliation":[{"name":"Division of Pediatrics and Diabetes (M.A.L.), The Children\u2019s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris K.","family":"Grammatopoulos","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism (D.M., H.L., D.K.G.), Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614052408100_R1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/520","article-title":"Impaired stress response and reduced 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