cyclic amp-dependent protein kinase a regulates the alternative splicing of camkiiδ循环amp-dependent蛋白质激酶调节camkiiδ的可变剪接.pdf

Cyclic AMP-Dependent Protein Kinase A Regulates the Alternative Splicing of CaMKIId 1 2 1 2 1 Qingqing Gu , Nana Jin , Hongzhuan Sheng , Xiaomin Yin , Jianhua Zhu * 1 Department of Cardiology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China, 2 Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, People’s Republic of China Abstract Ca2+/calmodulin-dependent protein kinase (CaMK) IId is predominantly expressed in the heart. There are three isoforms of CaMKIId resulting from the alternative splicing of exons 14, 15, and 16 of its pre-mRNA, which is regulated by the splicing factor SF2/ASF. Inclusion of exons 15 and 16 or of exon 14 generates dA or dB isoform. The exclusion of all three exons gives rise to dC isoform, which is selectively increased in pressure-overload-induced hypertrophy. Overexpression of either dB or dC induces hypertrophy and heart failure, suggesting their specific role in the pathogenesis of hypertrophy and heart failure. It is well known that the b-adrenergic-cyclic AMP-dependent protein kinase A (PKA) pathway is implicated in heart failure. To determine the role of PKA in the alternative splicing of CaMKIId, we constructed mini-CaMKIId genes and used these genes to investigate the regulation of the alternative splicing of CaMKIId by PKA in cultured cells. We found that PKA promoted the exclusion of exons 14, 15, and 16 of CaMKIId, resulting in an increase in dC isoform. PKA interacted with and phosphorylated SF2/ASF, and enhanced SF2/ASF’s activity to promote the exclusion of exons 14, 15, and 16 of CaMKIId, leading to a further increase in the expression of dC isoform. These findings suggest that abnormality in b-adrenergic-PKA signaling may contribute to cardiom