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A novel corticotropin-releasing factor receptor splice variant exhibits dominant negative activity: a putative link to stress-induced heart disease

Yehezkel Sztainberg^*,, Yael Kuperman^*, Orna Issler^*, Shosh Gil^*, Joan Vaughan, Jean Rivier, Wylie Vale and Alon Chen^*,1

^* Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel;

The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel; and

Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California, USA

¹ Correspondence: Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: alon.chen{at}weizmann.ac.il

A growing body of experimental and clinical studies supports a strong association between psychological stress and cardiovascular disease. An important endogenous cardioprotective role in heart physiology has been attributed to corticotropin-releasing factor receptor type 2β (CRFR2β). Here, we report the isolation of cDNA from mouse (m) heart encoding a novel CRFR2β splice variant. Translation of this insertion variant (iv)-mCRFR2β isoform produces a 421-aa protein that includes a unique C-terminal cytoplasmic tail. Our functional analysis and cellular localization studies demonstrated that when coexpressed with wild-type mCRFR2β, iv-mCRFR2β significantly inhibited the wild-type mCRFR2β membrane expression and its functional signaling by ER-Golgi complex retention, suggesting a dose-dependent dominant negative effect. Interestingly, mice exposed to a 4-wk paradigm of chronic variable stress, a model of chronic psychological stress in humans, presented significantly lower levels of mCRFR2β and higher levels of iv-mCRFR2β mRNA expression in their hearts, compared to nonstressed control mice. The dominant-negative effect of iv-mCRFR2β and its up-regulation by psychological stress suggest a new form of regulation of the mCRFR2β cardioprotective effect and a potential role for this novel isoform in stress-induced heart disease.—Sztainberg, Y., Kuperman, Y., Issler, O., Gil, S., Vaughan, J., Rivier, J., Vale, W., Chen, A. A novel corticotropin-releasing factor receptor splice variant exhibits dominant negative activity: a putative link to stress-induced heart disease.

Key Words: cardiovascular disease • urocortins • isoform • alternative splicing • ER retention