Alternative splicing of the type-IVA cyclic AMP phosphodiesterase gene provides isoform variants with distinct N-terminal domains fused to a common, soluble catalytic unit: ‘designer’ changes in Vmax, stability and membrane association

Houslay, Miles D.; Scotland, Grant; Pooley, L; Spence, Sandra; Wilkinson, Ian; McCallum, Fraser; Julien, Pascale; Rena, N. G.; Michie, Alison M.; Erdoğan, Suat; Zeng, Li; O’Connell, Jonathan C.; Tobias, Edward S.; MacPhee, Iain

doi:10.1042/bst0230393

Cited by 11 publications

(2 citation statements)

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“…Alternative splicing of cAMP‐specific phosphodiesterase PDE4 mRNA transcripts is another example of alternative splicing leading to enzymes with distinct properties [41–43]. This alternative splicing can generate PDE4 isoforms that are cytosolic or membrane associated [44].…”

Section: Discussionmentioning

confidence: 99%

The human calcium‐independent phospholipase A₂ gene

Forsell

Kennedy

Claesson

1999

European Journal of Biochemistry

120

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Recently, we reported the human 88-kDa calcium-independent phospholipase A2 (iPLA2) cDNA sequence, as well as extensive alternative splicing of the iPLA2 mRNA. In this report we identified the gene coding for iPLA2, which was localized on chromosome 22q13.1. The gene consists of at least 17 exons spanning > 69 kb. Based on the iPLA2 gene organization the splice variants can be explained. The putative promotor for the iPLA2 gene lacks a TATA-box and contains a CpG island as well as several potential Sp-1-binding sites. Furthermore, the 5'-flanking region also contains one medium reiteration frequency repeat (MER53) and an Alu repetitive sequence. Northern blot analysis of iPLA2 mRNA in various human tissues demonstrated tissue-specific expression of four distinct iPLA2 transcripts. The native human 3.2-kb iPLA2 transcript was predominantly expressed in heart, brain, skeletal muscle, prostate, testis, thyroid and spinal cord, and to a lesser extent in peripheral blood leucocytes, stomach, trachea and bone marrow. Studies on the subcellular localization of the native iPLA2 protein were performed in COS-7 cells overexpressing this enzyme. The cytosolic fraction of untransfected and cells overexpressing iPLA2 contained equal amounts of calcium-independent PLA2 activity. However, the membrane fraction displayed a 5.5-fold increased activity in iPLA2 overexpressing cells. This increased calcium-independent PLA2 activity correlated with the presence of iPLA2 immunoreactive protein in the membrane fraction, indicating that this form of iPLA2 protein was membrane associated. Studies of iPLA2 in rat vascular smooth muscle cells verified the membrane association of this form of iPLA2. The major difference between this form of iPLA2 enzyme and the soluble forms of iPLA2 studied previously is the presence of 54 additional amino acid residues derived from exon 9. We suggest that the addition of these 54 amino acids leads to a membrane-associated protein. In summary, these results demonstrate that alternative splicing of the human iPLA2 transcript generates multiple iPLA2 isoforms with distinct tissue distribution and cellular localization.

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Section: Discussionmentioning

confidence: 99%

The human calcium‐independent phospholipase A₂ gene

Forsell

Kennedy

Claesson

1999

European Journal of Biochemistry

120

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“…The intracellular localization of PDE4 isoforms is particularly regulated via isoform-specific N termini at the protein level, encoded by typical unique exon incorporation. These different N termini permit PDE4 isoforms to interact with protein partners or membranes in specific intracellular compartments (Houslay et al, 1995). In Aplysia, apPDE4 was found to require N-terminal residues for membrane binding, which indicates a conserved role for isoform-specific N termini in PDE4 localization (Jang et al, 2010).…”

Section: Phosphodiesterase 4 Subtypes and Isoformsmentioning

confidence: 99%

The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors

et al. 2021

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Correlations of PDE-4 inhibition between enzymes of smooth muscle and inflammatory cell sources

Cariuk

Cavalla

Chasin³

et al. 1998

Cell Biochem Biophys

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The sensitivities of PDE-4 enzymes from smooth muscle and inflammatory cell sources from different species to a range of structurally diverse compounds were compared. All inflammatory cell PDE-4 sources displayed good crosscorrelations in their sensitivity to inhibition by these compounds. Similarly, PDE-4 enzymes from smooth muscle sources were well-correlated; however, there was no crosscorrelation between PDE-4 from smooth muscle sources and those of inflammatory cell sources, possibly reflecting differences in subcellular location of enzymes as well as subtype expression. The present study concludes that PDE-4 preparations from smooth muscle sources as well as those from inflammatory cell sources may be used to model the potential smooth muscle cell relaxing properties and anti-inflammatory properties of a compound in relation to human asthma.

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Alternative splicing of the type-IVA cyclic AMP phosphodiesterase gene provides isoform variants with distinct N-terminal domains fused to a common, soluble catalytic unit: ‘designer’ changes in Vmax, stability and membrane association

Cited by 11 publications

References 1 publication

The human calcium‐independent phospholipase A₂ gene

The human calcium‐independent phospholipase A₂ gene

The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors

Correlations of PDE-4 inhibition between enzymes of smooth muscle and inflammatory cell sources

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Alternative splicing of the type-IVA cyclic AMP phosphodiesterase gene provides isoform variants with distinct N-terminal domains fused to a common, soluble catalytic unit: ‘designer’ changes in Vmax, stability and membrane association

Cited by 11 publications

References 1 publication

The human calcium‐independent phospholipase A2 gene

The human calcium‐independent phospholipase A2 gene

The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors

Correlations of PDE-4 inhibition between enzymes of smooth muscle and inflammatory cell sources

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Product

Resources

About

The human calcium‐independent phospholipase A₂ gene

The human calcium‐independent phospholipase A₂ gene