Four different isoforms of the catalytic subunit of cAMP-dependent protein kinase, termed Cα, Cβ, Cγ and PrKX have been identified. Here we demonstrate that the human Cβ gene encodes six splice variants, designated Cβ1, Cβ2, Cβ3, Cβ4, Cβ4ab and Cβ4abc. The Cβ splice variants differ in their N-terminal ends due to differential splicing of four different forms of exon 1 designated exon 1-1, 1-2, 1-3, 1-4 and three exons designated a, b and c. All these exons are located upstream of exon 2 in the Cβ gene. The previously identified human Cβ variant has been termed Cβ1, and is similar to the Cβ isoform identified in the mouse, ox, pig and several other mammals. Human Cβ2, which is the homologue of bovine Cβ2, has no homologue in the mouse. Human Cβ3 and Cβ4 are homologous to the murine Cβ3 and Cβ2 splice variants, whereas human Cβ4ab and Cβ4abc represent novel isofoms previously not identified in any other species. At the mRNA level, the Cβ splice variants reveal tissue specific expression. Cβ1 was most abundantly expressed in the brain, with low-level expression in several other tissues. The Cβ3 and Cβ4 splice variants were uniquely expressed in human brain in contrast to Cβ2, which was most abundantly expressed in tissues of the immune system, with no detectable expression in brain.
We suggest that the various Cβ splice variants when complexed with regulatory subunits may give rise to novel holoenzymes of protein kinase A that may be important for mediating specific effects of cAMP.