RGD Reference Report - Aberrant Splicing Induced by Dysregulated Rbfox2 Produces Enhanced Function of CaV1.2 Calcium Channel and Vascular Myogenic Tone in Hypertension. - Rat Genome Database

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Aberrant Splicing Induced by Dysregulated Rbfox2 Produces Enhanced Function of CaV1.2 Calcium Channel and Vascular Myogenic Tone in Hypertension.

Authors: Zhou, Yingying  Fan, Jia  Zhu, Huayuan  Ji, Li  Fan, Wenyong  Kapoor, Isha  Wang, Yue  Wang, Yuan  Zhu, Guoqing  Wang, Juejin 
Citation: Zhou Y, etal., Hypertension. 2017 Dec;70(6):1183-1192. doi: 10.1161/HYPERTENSIONAHA.117.09301. Epub 2017 Oct 9.
RGD ID: 329848961
Pubmed: PMID:28993448   (View Abstract at PubMed)
DOI: DOI:10.1161/HYPERTENSIONAHA.117.09301   (Journal Full-text)

Calcium influx from activated voltage-gated calcium channel CaV1.2 in vascular smooth muscle cells is indispensable for maintaining myogenic tone and blood pressure. The function of CaV1.2 channel can be optimized by alternative splicing, one of post-transcriptional modification mechanisms. The splicing factor Rbfox2 is known to regulate the CaV1.2 pre-mRNA alternative splicing events during neuronal development. However, Rbfox2's roles in modulating the key function of vascular CaV1.2 channel and in the pathogenesis of hypertension remain elusive. Here, we report that the proportion of CaV1.2 channels with alternative exon 9* is increased by 10.3%, whereas that with alternative exon 33 is decreased by 10.5% in hypertensive arteries. Surprisingly, the expression level of Rbfox2 is increased ≈3-folds, presumably because of the upregulation of a dominant-negative isoform of Rbfox2. In vascular smooth muscle cells, we find that knockdown of Rbfox2 dynamically increases alternative exon 9*, whereas decreases exon 33 inclusion of CaV1.2 channels. By patch-clamp studies, we show that diminished Rbfox2-induced alternative splicing shifts the steady-state activation and inactivation curves of vascular CaV1.2 calcium channel to hyperpolarization, which makes the window current potential to more negative. Moreover, siRNA-mediated knockdown of Rbfox2 increases the pressure-induced vascular myogenic tone of rat mesenteric artery. Taken together, our data indicate that Rbfox2 modulates the functions of vascular CaV1.2 calcium channel by dynamically regulating the expressions of alternative exons 9* and 33, which in turn affects the vascular myogenic tone. Therefore, our work suggests a key role for Rbfox2 in hypertension, which provides a rational basis for designing antihypertensive therapies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hypertension  ISORbfox2 (Rattus norvegicus)329848961; 329848961mRNA more ...RGD 
hypertension  IEP 329848961mRNA more ...RGD 

Gene-Chemical Interaction Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
angiotensin II decreases expression ISORbfox2 (Rattus norvegicus)329848961; 329848961Angiotensin II decreases expression of Rbfox2 mRNA and protein in vascular smooth muscle cellsRGD 
angiotensin II decreases expression EXP 329848961Angiotensin II decreases expression of Rbfox2 mRNA and protein in vascular smooth muscle cellsRGD 
Endothelin-1 decreases expression ISORbfox2 (Rattus norvegicus)329848961; 329848961Endothelin-1 decreases expression of Rbfox2 mRNA and protein in vascular smooth muscle cellsRGD 
Endothelin-1 decreases expression EXP 329848961Endothelin-1 decreases expression of Rbfox2 mRNA and protein in vascular smooth muscle cellsRGD 
phenylephrine  ISORbfox2 (Rattus norvegicus)329848961; 329848961Phenylephrine increases expression of Rbfox2 mRNA and protein in vascular smooth muscle cellsRGD 
phenylephrine  EXP 329848961Phenylephrine increases expression of Rbfox2 mRNA and protein in vascular smooth muscle cellsRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
nucleus  IDA 329848961 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Rbfox2  (RNA binding fox-1 homolog 2)

Genes (Mus musculus)
Rbfox2  (RNA binding protein, fox-1 homolog (C. elegans) 2)

Genes (Homo sapiens)
RBFOX2  (RNA binding fox-1 homolog 2)


Additional Information