An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing

Abstract

BackgroundCyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). The cAMP-specific PDE family 4 (PDE4) is widely expressed in vertebrates. Each of the four PDE4 gene isoforms (PDE4 A-D) undergo extensive alternative splicing via alternative transcription initiation sites, producing unique amino termini and yielding multiple splice variant forms from each gene isoform termed long, short, super-short and truncated super-short. Many species across the vertebrate lineage contain multiple splice variants of each gene type, which are characterized by length and amino termini.ResultsA phylogenetic approach was used to visualize splice variant form genesis and identify conserved splice variants (genome conservation with EST support) across the vertebrate taxa. Bayesian and maximum likelihood phylogenetic inference indicated PDE4 gene duplication occurred at the base of the vertebrate lineage and reveals additional gene duplications specific to the teleost lineage. Phylogenetic inference and PDE4 splice variant presence, or absence as determined by EST screens, were further supported by the genomic analysis of select vertebrate taxa. Two conserved PDE4 long form splice variants were found in each of the PDE4A, PDE4B, and PDE4C genes, and eight conserved long forms from the PDE4 D gene. Conserved short and super-short splice variants were found from each of the PDE4A, PDE4B, and PDE4 D genes, while truncated super-short variants were found from the PDE4C and PDE4 D genes. PDE4 long form splice variants were found in all taxa sampled (invertebrate through mammals); short, super-short, and truncated super-short are detected primarily in tetrapods and mammals, indicating an increasing complexity in both alternative splicing and cAMP metabolism through vertebrate evolution.ConclusionsThere was a progressive independent incorporation of multiple PDE4 splice variant forms and amino termini, increasing PDE4 proteome complexity from primitive vertebrates to humans. While PDE4 gene isoform duplicates with limited alternative splicing were found in teleosts, an expansion of both PDE4 splice variant forms, and alternatively spliced amino termini predominantly occurs in mammals. Since amino termini have been linked to intracellular targeting of the PDE4 enzymes, the conservation of amino termini in PDE4 splice variants in evolution highlights the importance of compartmentalization of PDE4-mediated cAMP hydrolysis.

Metapopulation patterns of additive and nonadditive genetic variance in the sea bass (Dicentrarchus labrax)

“…However, hybridizing tiger salamanders ( Ambystoma sp .) demonstrated no recovery of fitness in hybrid populations (Johnson, Fitzpatrick, & Shaffer, 2010), indicating that multigenerational effects of hybridization are complex because hybridizing genomes may become “stabilized” at far lower rates than previously expected (Buerkle & Rieseberg, 2008). …”

Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus

“…All PDE4-selective inhibitors act at the catalytic sites of the PDE4 enzymes [ 23 – 25 ] and therefore act, at least in part, as competitive inhibitors of cAMP hydrolysis. There are over 20 PDE4 isoforms, which are encoded by 4 genes in mammals, with additional diversity being produced by alternative mRNA splicing and the use of alternative promoters for each isoform [ 26 , 27 ]. The catalytic sites of these isoforms are extremely similar, which has greatly complicated the development of inhibitors selective for any individual isoform [ 24 ].…”

“…[ 26 , 57 ]). Each PDE4B isoform has a different pattern of expression in the CNS [ 27 – 29 , 32 , 33 , 35 , 37 , 57 – 60 ], suggesting that each mediates a specific, non-overlapping function; however, the precise neurobiological functions of each of these isoforms will require additional investigation. In - situ studies have detected PDE4B1 mRNA expression in mouse hippocampal CA2 and CA3 regions, parietal and piriform cortex, and the cerebellar granular layer, among other brain regions [ 33 ], suggesting a potential role in a variety of CNS functions.…”

The frequent evolutionary birth and death of functional promoters in mouse and human

“…This can manifest as the differential inclusion of regulatory sequences, including miRNA binding sites, or the alteration of an encoded N-terminal amino acid sequence, as is the case for PDE4C (Fig. 6A), an example that has previously been noted (Johnson et al 2010) and a type of change that is a recurrent evolutionary feature of the PDE4 gene family.…”