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Phosphodiesterase 11: a Brief Review of Structure, Expression and Function

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International Journal of Impotence Research (2006) 18, 501–509 & 2006 Nature Publishing Group All rights reserved 0955-9930/06 $30.00 www.nature.com/ijir REVIEW Phosphodiesterase 11: a brief review of structure, expression and function A Makhlouf, A Kshirsagar and C Niederberger Department of Urology, University of Illinois at Chicago, Chicago, IL, USA Phosphodiesterase 11 (PDE11) is the latest isoform of the phosphodiesterase family to be identified. Interest in PDE11 has increased recently because tadalafil, an oral phosphodiesterase 5 inhibitor, cross reacts with PDE11. The function of PDE11 remains largely unknown, but growing evidence points to a possible role in male reproduction. The published literature on PDE11 structure, function and expression is reviewed. International Journal of Impotence Research (2006) 18, 501–509. doi:10.1038/sj.ijir.3901441; published online 5 January 2006 Keywords: phosphodiesterase; tadalafil; spermatogenesis; erectile dysfunction Introduction possible role of PDE11 in spermatogenesis and potential effects, if any, of tadalafil on it. Introduction of orally administered phosphodiester- ase-5 (PDE5) inhibitors revolutionized the treatment of erectile dysfunction in the past decade.1 Of the 11 Overview of PDEs known phosphodiesterases (PDEs), PDE5 has been 1,6 the focus of much attention because it is the protein Mammalian PDEs are divided into 11 families. target of these inhibitors. Sildenafil was the first Some families (PDE1, PDE3, PDE4, PDE7 and PDE8) PDE5 inhibitor to be marketed followed by varde- are products of multiple genes (multigene), whereas nafil and tadalafil. All three compounds inhibit the others derive from a single gene (unigene) (Table 1). catalytic activity of PDE5, thereby preventing the Thus, the human genome contains 21 known genes degradation of intracellular cGMP. In turn, cGMP coding for PDEs. Variations in splicing and alternate activates cGMP-dependent protein kinase, which initiation sites create more variety in each family, with 6,7 phosphorylates a number of intracellular proteins a total number of 53 isoenzymes identified so far. resulting in decreased intracellular calcium concen- All PDEs share a highly conserved catalytic domain 1 tration and leading to penile smooth muscle relaxa- near the carboxyl-terminus, including 11 invariant 8 tion, vasodilatation, and subsequently, penile amino acids in the active site. Minor variations in the erection. Recently, there has been an increased catalytic domain are believed to be responsible for the interest in PDE11 because tadalafil, one of the newer different selectivities towards cAMP or cGMP sub- 8 PDE5 inhibitors approved for treatment of ED, cross- strate and various inhibitors (Table 1). More sub- reacts with PDE11.2–6 The expression and function stantial variation exists in the N-terminus part, where 1,9 of PDE11 are still poorly understood, and this most of the regulatory domains reside. present review will summarize the current state In the case of PDE11, there is a single gene in the of knowledge regarding PDE11 structure, function family (PDE11A according to standard nomencla- and distribution. Emphasis will be placed on the ture) with four splicing variants (PDE11A1, PDE11A2, PDE11A3 and PDE11A4). This appears to be the case in all mammalian species studied so far (human, rat and mouse).10–12 Correspondence: Dr A Makhlouf, Department of Urology, University of Illinois at Chicago, 840 S. Wood Street, MC 955 Chicago, IL 60612-7316, USA. E-mail: [email protected] Cloning and isolation of PDE11A Received 2 August 2005; revised 29 November 2005; accepted 29 November 2005; published online 5 January PDE11A was the latest member of the mammalian 2006 PDE family to be identified.13 As the entire human Phosphodiesterase 11 A Makhlouf et al 502 Table 1 Summary of PDE family characteristics1,7–9 PDE Genes (if Substrate Inhibitors, Ki or (IC50) Regulation Tissue expression family multigene) 2 þ 1 PDE1A cAMP4cGMP Vinpocetine (14 mM) ( þ )Ca /CAM 1A: Thyroid, testis, brain PDE1B cAMP4cGMP Zaprinast (6 mM)(À)PKA, CamKII 1B: Brain, lymphocytes PDE1C cAMP ¼ cGMP Sildenafil (0.35 mM) 1C: Blood vessels, testis 2 cGMPXcAMP EHNA (1 mM) ( þ )cGMP, PKC Brain, heart, platelets, liver, Bay 60-7550 (0.047 mM)(þ /À)N-terminal-targeting thymocytes domain 3 PDE3A cAMP4cGMP Cilostamide (0.020 mM) ( þ )PKA, PKB 3A: Heart, blood vessels PDE3B Milrinone (0.150 mM) (À)cGMP 3B: Adipocytes, Zardaverine (0.5–2 mM)(þ /À)N-terminal-targeting hepatocytes, lymphocytes domain 4 PDE4A cAMP Rolipram (1 mM) ( þ )PKA, ERK, phosphatidic 4A: Lung, immune cells, acid brain, blood vessels PDE4B Roflumilast (0.8 nM)(À)ERK, caspases PDE4C Cilomilast (120 nM)(þ /À)N-terminal-targeting PDE4D Zardaverine (0.8–4 mM) domains 5 cGMP Zaprinast (0.130 mM) ( þ )cGMP, PKG, PKA Smooth muscle, platelets, Sildenafil (0.10 mM) (À)Caspases Purkinje cells, gastro- Vardenafil (0.001 mM) intestinal epithelium, Tadalafil (0.010 mM) pulmonary endothelium 6 PDE6A cGMP Zaprinast (0.400 mM) ( þ )Transducin Retinal photoreceptors PDE6B Dipyridamole (0.125 mM) (À)cGMP, gamma and delta PDE6C Sildenafil (0.050 mM) subunits Vardenafil (0.011 mM) Tadalafil (2 mM) 7 PDE7A cAMP IBMX (4 mM) ( þ /À)PKA Brain, lymphocytes, kidney PDE7B Dipyridamole (0.6 mM) 8 PDE8A cAMP Dipyridamole (9 mM) PAS domain Thyroid PDE8B 9 cGMP Zaprinast (35 mM) Unknown Kidney 10 cGMP4cAMP Dipyridamole (1 mM) (À)cAMP Testis, brain Zaprinast (22 mM) 11 cAMP and Zaprinast (12 mM) Unknown Skeletal muscle, prostate, cGMP Dipyridamole (0.4 mM) testis, corpus cavernosum, heart (but see text and Table 3) CAM ¼ calmodulin c; ERK ¼ extracellular signal-regulated protein kinase; PAS ¼ periodic acid-Schiff stain; PDE ¼ phosphodiesterase; PKA ¼ protein kinase A; PKC ¼ protein kinase A; PKG ¼ protein kinase G. Only some of the most commonly reported inhibitors for each PDE are listed. Tissue expression is representative of most reports and is not necessarily exhaustive. genome sequence is now available, it appears to be cloned the A3 and A4 isoforms of PDE11A by PCR the last. The first published report of PDE11A was with degenerate primers from the conserved cataly- by Fawcett et al.,13 who obtained a partial sequence tic domain of other PDEs, using a human multi- of PDE11A from a commercially available expressed tissue cDNA library template. No other variants of sequence tag (EST) database based on homology human PDE11A have since been reported. with other mammalian PDEs. These investigators then used the PDE11A partial sequence to identify the PDE11A gene from a human skeletal muscle Gene structure of PDE11A cDNA library. Soon after, the same group cloned PDE11A2 and PDE11A3 cDNAs from a human testis Among the mammalian superfamily of PDEs, PDE11 library.12 Almost simultaneously, Yuasa et al.10 is phylogenetically related to the other GAF- International Journal of Impotence Research Phosphodiesterase 11 A Makhlouf et al 503 Stop codon (all forms) ATG ATG ATG ATG (PDE11A3) (PDE11A4) (PDE11A2) (PDE11A1) HSPDE11A gene ∗∗ >300 Kb Exon # 12 3 4567891011 12 13 14 15 16 17 18 19 20 21 22 23 GAF a GAF b Catalytic domain 490 aa (55.8 kDa) AUG Stop PDE11A1 1784 bp GAF a domain 7 Exons 8-23 GAF b domain 576 aa (65.8 kDa) AUG Stop Catalytic domain PDE11A2 2141 bp ∗ Phosphorylation site ?56 Exons 8-23 684 aa (78.1 kDa) AUG Stop PDE11A3 2205 bp 162 4 5 Exons 8-23 934 aa (104.8 kDa) AUG Stop PDE11A4 ∗∗ 4476 bp 364 5 Exons 8-23 Figure 1 Gene structure of HSPDE11A (Homo sapiens PDE11A) and its four known variants. Gene structure is based on Yuasa et al.14 Exon numbers follow Yuasa et al.,14 in contrast to GeneBank that lists the 20 exons of PDE11A4 only. The 50-most exon(s) of PDE11A2 have not been studied.12 Sizes of the cDNA (in bp) and the predicted molecular weight (in kDa) of the open-reading frame protein are shown. containing PDEs (PDE2, PDE5, PDE6 and PDE10) for A1 and A3 have canonical TATA motifs, whereas based on sequence homology14 (GAF ¼ cGMP bind- that for A4 is TATA-less but has a GC-rich region ing PDE, Anabaena adenylyl cylcase and E. coli with a CCAAT box and Sp-1 binding site. It is FhlA domain after the proteins where it was initially speculated that these differences in promoters are identified). GAFs are regulatory domains that in responsible for the different patterns of tissue some instances bind small molecules such as cGMP distribution exhibited by the various isoforms.14 or are involved in protein–protein interactions (see Sequence analysis of the upstream gene region Zoraghi et al.15 for a review). PDE11 most closely demonstrated the presence of SRY and Sox-5 motifs. resembles PDE5 by sequence, with 50% identity This hints at a potential role for PDE11A expression and 70% similarity in the catalytic domain.13 In in testicular development. However, no functional humans, the PDE11 subfamily consists of a single studies of the PDE11A promoter have been pub- gene, which has been localized to chromosome lished to date. 2q31 by fluorescent in situ hybridization.14 This Alternate splicing is responsible for further varia- was later confirmed by the Human Genome Project tion in the PDE11 family. PDE11A1, the shortest complete sequence. The gene spans a long stretch of form, does not include exons 1–6. Thus, it lacks the DNA (4300 kb) and is spread over more than 20 first GAF domain, and only includes a part of the exons (Figure 1). Alternate transcription initiation second GAF. PDE11A2 and PDE11A3 are slightly sites and alternate splicing are responsible for longer, including the entire second GAF and parts of the generation of the four isoforms of PDE11A the first GAF domain,10,12,14 whereas the longest (Figure 1).12,14 form, PDE11A4, includes both domains in addition The gene structure of PDE11A variants is detailed to two phosphorylation sites in the N-terminus in Figure 1.
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  • Memory Enhancers for Alzheimer's Dementia

    Memory Enhancers for Alzheimer's Dementia

    pharmaceuticals Review Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP Ernesto Fedele 1,2,* and Roberta Ricciarelli 2,3,* 1 Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, 16148 Genova, Italy 2 IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy 3 Department of Experimental Medicine, Section of General Pathology, University of Genoa, 16132 Genova, Italy * Correspondence: [email protected] (E.F.); [email protected] (R.R.) Abstract: Cyclic guanosine-30,50-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate en- zymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive.