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Cyclic AMP-dependent protein kinase A regulates the alternative splicing of CaMKIIδ

Qingqing Gu1, Nana Jin, Hongzhuan Sheng

  • 1Department of Cardiology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.

Plos One
|December 2, 2011
PubMed

Insights

Protein kinase A (PKA) regulates the alternative splicing of Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIδ) in heart cells. PKA promotes the exclusion of specific exons, increasing the CaMKIIδC isoform, which may contribute to heart failure.

Area of Science:

  • Molecular Biology
  • Cardiovascular Biology
  • Gene Regulation

Background:

  • Ca(2+)/calmodulin-dependent protein kinase II delta (CaMKIIδ) is crucial in cardiac function.
  • Alternative splicing of CaMKIIδ pre-mRNA generates distinct isoforms (δA, δB, δC).
  • The δC isoform is elevated in pressure-overload-induced cardiac hypertrophy and heart failure.

Purpose of the Study:

  • To investigate the role of the β-adrenergic-cyclic AMP-dependent protein kinase A (PKA) pathway in regulating CaMKIIδ alternative splicing.
  • To determine how PKA influences the expression of CaMKIIδ isoforms, particularly δC.

Main Methods:

  • Construction of mini-CaMKIIδ genes in cultured cells.
  • Investigation of PKA's effect on CaMKIIδ alternative splicing.
  • Analysis of PKA interaction with and phosphorylation of splicing factor SF2/ASF.

Main Results:

  • PKA significantly promoted the exclusion of exons 14, 15, and 16 of CaMKIIδ pre-mRNA.
  • This PKA-mediated splicing resulted in increased expression of the CaMKIIδC isoform.
  • PKA directly interacted with and phosphorylated SF2/ASF, enhancing its splicing activity.

Conclusions:

  • PKA plays a key role in regulating CaMKIIδ alternative splicing, favoring the δC isoform.
  • Dysregulation of the β-adrenergic-PKA pathway may contribute to heart failure via altered CaMKIIδ splicing.
  • Increased CaMKIIδC expression due to aberrant PKA signaling is implicated in cardiomyopathy.

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