Cyclic AMP-dependent protein kinase (PKA) is a holoenzyme composed of two catalytic (C) subunits and a regulatory (R) subunit dimer. The holoenzyme dissociates when four cAMP molecules bind to the R subunit dimer. This activates the C subunits, allowing them to phosphorylate specific substrate proteins and thereby alter their activity. Studies involving cDNA cloning have revealed four different R and four different C subunit genes which encode the subunits designated RI, RI, RII, RII, C, C, C and PRKX1. Furthermore, different splice variants encoded by the human C and C genes have been identified and designated Cα1, CαS, Cβ1, Cβ2, C3, Cβ3b, Cβ3ab, Cβ3abc, C4, Cβ4b, C4ab and C4abc. They are all tissue-specifically expressed, highly heterogenic in the N-terminal end, and highly conserved in the catalytic domain.
We have discovered 6 novel splice variants of the C gene in NTera2-N cells as both mRNAs and proteins. All the novel splice variants were designated CβΔ4 since they lack 99 encoding base pairs representing exon 4 due to inframe skipping in the C gene. We developed a method to detect CβΔ4 mRNAs and found that these are primarily expressed in the brain of higher primates. While separately co-expressing different CβΔ4 variants with either the RI or RII subunit, we demonstrated that CβΔ4 interacts with the R subunit, in a cAMP insensitive fashion. This together with the fact that these variants are brain specifically expressed may suggest that they function to regulate cAMP sensitivity of nerve cells.