A novel corticotropin-releasing factor receptor splice variant exhibits dominant negative activity: a putative link to stress-induced heart disease.
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 2beta (CRFR2beta). Here, we report the isolation of cDNA from mouse (m) heart encoding a novel CRFR2beta splice variant. Translation of this insertion variant (iv)-mCRFR2beta 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 mCRFR2beta, iv-mCRFR2beta significantly inhibited the wild-type mCRFR2beta 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 mCRFR2beta and higher levels of iv-mCRFR2beta mRNA expression in their hearts, compared to nonstressed control mice. The dominant-negative effect of iv-mCRFR2beta and its up-regulation by psychological stress suggest a new form of regulation of the mCRFR2beta cardioprotective effect and a potential role for this novel isoform in stress-induced heart disease.
Sztainberg
Yehezkel
Y
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Kuperman
Yael
Y
Issler
Orna
O
Gil
Shosh
S
Vaughan
Joan
J
Rivier
Jean
J
Vale
Wylie
W
Chen
Alon
A
D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000302:isolation & purification; D005786:Gene Expression Regulation / Q000502:physiology*; D005799:Genes, Dominant; D006331:Heart Diseases / Q000209:etiology* / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000737:chemistry; D020011:Protective Agents; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D013312:Stress, Physiological
C101531:CRF receptor type 2; D018076:DNA, Complementary; D020011:Protective Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone