Inhibition of cGMP-dependent protein kinase II by its own splice isoform

Abstract

cGMP- and cAMP-dependent protein kinases (cGK I, cGK II, and cAK) are important mediators of many signaling pathways that increase cyclic nucleotide concentrations and ultimately phosphorylation of substrates vital to cellular functions. Here we demonstrate a novel mRNA splice isoform of cGK II arising from alternative 5 ′ splicing within exon 11. The novel splice variant encodes a protein (cGK II Δ 441–469) lacking 29 amino acids of the cGK II Mg–ATP-binding/catalytic domain, including the conserved glycine-rich loop consensus motif Gly–x–Gly–x–x–Gly–x–Val which interacts with ATP in the protein kinase family of enzymes. cGK II Δ 441–469 has no intrinsic enzymatic activity itself, however, it antagonizes cGK II and cGK I, but not cAK. Thus, the activation and cellular functions of cGK II may be determined not only by intracellular cGMP levels but also by alternative splicing which may regulate the balance of expression of cGK II versus its own inhibitor, cGK II Δ 441–469.