Expression, structure and chromosomal localization of the human cGMP‐binding cGMP‐specific phosphodiesterase PDE5A gene

Abstract

cGMP‐binding, cGMP‐specific phosphodiesterase which is encoded by the PDE5A gene plays important roles in cardiovascular system, and is a significant target molecule of therapeutic agents. However, little is known about molecular characteristics of the human PDE5A gene. The 4.4‐kb cDNA encoding human PDE5A was isolated from lung and placenta cDNA libraries. The deduced amino acid sequence analysis demonstrated that N‐terminal amino acid sequence is dissimilar to that of rat PDE5A [Kotera, J., Yanaka, N., Fujishige, K., Imai, Y., Akatsuka, H., Ishizuka, T., Kawashima, K. & Omori, K. (1997) Eur. J. Biochem. 249, 434−442]. Human PDE5A mRNA is produced in high amounts in various tissues such as pancreas, skeletal muscle, placenta, heart, thyroid, adrenal cortex, testis, small intestine and stomach. In addition, the megakaryocyte‐like cell line Dami cells and two types of human vascular smooth muscle cells also produce the mRNA. Over 100‐kb chromosomal DNA corresponding to the human PDE5A gene was isolated and analyzed. The human PDE5A gene was revealed to contain 21 exons. Comparison of genomic organization with the rod photoreceptor phosphodiesterase β‐subunit gene (PDE6B), which is another kind of cGMP‐specific phosphodiesterase, has shown that the PDE5A and PDE6B genes are very similar in their relative exon−intron organization. In particular, the evolutionary relatedness of these genes was suggested in the catalytic domain. Furthermore, chromosomal location of the PDE5A gene was defined as being chromosome 4q26 by fluorescent in situ hybridization analysis.

Tissue expression, distribution, and regulation of PDE5

“…The human PDE5 gene is located on chromosome 4q26 4,5 and initially reported to contain 21 exons spanning approximately 100 kilobases. 5 The current identification of PDE5 isoforms should increase that number to 23 exons, with the first three exons being alternative first exons encoding the isoformspecific sequences.…”

“…5 The current identification of PDE5 isoforms should increase that number to 23 exons, with the first three exons being alternative first exons encoding the isoformspecific sequences. These three alternative first exons are arranged in the order of A1-A3-A2 in the PDE5A gene.…”

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

“…It is a key physiologic regulator of cGMP and pharmacologic target of vasodilatory drugs (such as sildenafil citrate) used commonly to treat PH and erectile dysfunction 8. The coding sequence, functional regions, and transcript variants of PDE5A are well described in human beings 9, 10. Additionally, the genetic sequence of phosphodiesterase genes has been demonstrated to be responsible for the selective action of some phosphodiesterase inhibiting agents.…”

Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5)

“…[20][21][22] The regulatory region of the PDE5A gene was described 23 (GenBank accession no. AB001615) and showed several potential regulatory factor-binding sequences.…”

“…AB001615) and showed several potential regulatory factor-binding sequences. 23 Among these regulatory sequences, there are two AP1 elements located at positions -1302 and -1204 (AB001615): these elements, known to mediate cGMP signal transduction pathway, 24 are likely to be the most important positive regulators of PDE5A gene expression and, moreover, cGMP may be not only a common mediator of penile and systemic arterial vasodilatation, but, at the genomic level, also a common regulator of genes involved in EH/ED phenotype.…”