An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing

BMC Evolutionary Biology, Aug 2010

Background Cyclic 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. Results A 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. Conclusions There 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.

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An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing

Keven R Johnson 2 Jessie Nicodemus-Johnson 1 Robert S Danziger 0 3 0 Department of Research and Development, Jesse Brown VA Medical Center 820 S. Damen Avenue , Chicago IL 60612 USA 1 Department of Human Genetics, University of Chicago 5812 S. Ellis Avenue Chicago, IL 60637 USA 2 Department of Physiology and Biophysics, University of Illinois at Chicago 835 S. Wolcott Avenue, M/C 901, Chicago, IL 60612-7342 USA 3 Department of Medicine, Division of Cardiology, University of Illinois at Chicago 840 S. Wood Street, M/C 715 Chicago IL 60612 USA Background: Cyclic 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. Results: A 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. Conclusions: There 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. - Background Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic nucleotide second messengers; cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [1,2]. The PDE4 family is one of three cAMP-specific PDE families. PDE4 s have been shown to regulate several cellular physiological processes such as; protein phosphorylation via cAMP-dependent protein kinase A (PKA), gene transcription through cAMP response elements, and cyclic nucleotide gated ion channels [3-6]. These processes have been linked to cognitive function, depression, schitzophrenia, hypertension, and an integral involvement in modulating cardiomyocyte contractility [7,8]. The PDE4 gene family is composed of four gene isoforms; PDE4A, PDE4B, PDE4C, and PDE4 D which arose via a gene duplication event in a common eukaryotic ancestor before the separation of sponges and eumetazoans [9]. Although PDE4 s have not been extensively studied in teleosts, amphibians, or reptiles, transcripts from all four PDE4 gene isoforms have been detected in several mammalian species; for review, [8]. Mammalian PDE4 splice variant forms produced from each gene isoform (A-D) have been classified as: long, short, super-short, or truncated super-short [7,10] (Figure 1). PDE4 splice variant synthesis proceeds through alternative splicing via the incorporation of distinct promoters (alternative transcription start sites) that drive differential tissue expression and transcriptional regulation [11-13]. The long form transcripts consist of exons encoding the amino termini (i.e., 5 exon), upstream conserved region-1 (UCR-1), linker region-1 (LR-1), UCR-2, LR2, catalytic, and carboxy-terminal domains (Figure 1). Each PDE4 gene isoforms produces multiple PDE4 long forms with unique amino termini. The PDE4 amino terminal protein region is proposed to be responsible for varian (...truncated)


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Keven R Johnson, Jessie Nicodemus-Johnson, Robert S Danziger. An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing, BMC Evolutionary Biology, 2010, pp. 247, 10, DOI: 10.1186/1471-2148-10-247