Phosphodiesterase 11: a brief review of structure, expression and function

Makhlouf, Antoine A.; Kshirsagar, Ash; Niederberger, Craig S.

doi:10.1038/sj.ijir.3901441

Cited by 55 publications

(31 citation statements)

References 30 publications

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“…PDE11A is phylogenetically related to GAF-containing PDEs: PDE2, -5, -6, and -10; it closely resembles PDE5 by sequence (50% identity and 70% similarity in the catalytic domain) and is located in chromosome 2q31-32 (for a recent review, refer to ref. 40). Thus, our data support the involvement of chr 2q31-32 in the susceptibility for MDD and in antidepressant response.…”

Section: Discussionsupporting

confidence: 74%

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Wong

Whelan²,

Deloukas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

139

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Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are downregulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger implicated in learning, memory, and mood, and cGMP modulates nervous system processes that are controlled by the nitric oxide (NO)͞cGMP pathway. To investigate an association between genes encoding PDEs and susceptibility to major depressive disorder (MDD), we genotyped SNPs in 21 genes of this superfamily in 284 depressed Mexican Americans who participated in a prospective, double-blind, pharmacogenetic study of antidepressant response, and 331 matched controls. Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD. Our data are also suggestive of the association between SNPs in other PDE genes and MDD. Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A. Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene. We show here that PDE11A haplotype GAACC is significantly associated with MDD. We conclude that PDE11A has a role in the pathophysiology of MDD. This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested.gene association ͉ pharmacogenetics ͉ cGMP ͉ SNP ͉ Mexican American

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Section: Discussionsupporting

confidence: 74%

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Wong

Whelan²,

Deloukas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

139

View full text Add to dashboard Cite

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“…PDE11 has been shown to be localized in the seminal pathways, including the prostate, and in subcellular components of the spermatozoa. It has been suggested that the administration of tadalafil (and presumably other PDE5 inhibitors) can enhance the secretory function of the prostate and subsequently increase the motility of spermatozoa [65,72]. There are hints that the effects of PDE5 inhibitors are mediated not only by cylic GMP but also by cyclic AMP.…”

Section: Facilitation Of Sperm Viability and Motilitymentioning

confidence: 98%

The recent phosphodiesterase type 5 inhibitors

Ückert¹,

Becker²,

Stief³

et al. 2012

Human Andrology

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“…While the C-terminal region encompasses the catalytic domain of PDE11A, the N-terminal region encompasses various regulatory domains and sites of post-translational modification. Within the N-terminal region are 2 c G MP binding PDE, A nabaena adenylyl cyclase and E. coli F hlA (GAF) domains [35]. Perhaps not surprisingly, phylogenetic analyses suggests PDE11A is most closely related to other GAF-domain containing PDEs, particularly PDE5A and PDE6A-C as well as PDE2A and PDE10A [6, 7].…”

Section: Molecular Features Of Pde11amentioning

confidence: 99%

A Role for Phosphodiesterase 11A (PDE11A) in the Formation of Social Memories and the Stabilization of Mood

Kelly

2017

Advances in Neurobiology

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The most recently discovered 3′,5′-cyclic nucleotide phosphodiesterase family is the Phosphodiesterase 11 (PDE11) family, which is encoded by a single gene PDE11A. PDE11A is a dual-specific PDE, breaking down both cAMP and cGMP. There are four PDE11A splice variants (PDE11A1–4) with distinct tissue expression profiles and unique N-terminal regulatory regions, suggesting that each isoform could be individually targeted with a small molecule or biologic. PDE11A4 is the PDE11A isoform expressed in brain and is found in the hippocampal formation of humans and rodents. Studies in rodents show that PDE11A4 mRNA expression in brain is, in fact, restricted to the hippocampal formation (CA1, possibly CA2, subiculum, and the adjacently connected amygdalohippocampal area). Within the hippocampal formation of rodents, PDE11A4 protein is expressed in neurons but not astrocytes, with a distribution across nuclear, cytoplasmic, and membrane compartments. This subcellular localization of PDE11A4 is altered in response to social experience in mouse, and in vitro studies show the compartmentalization of PDE11A4 is controlled, at least in part, by homodimerization and N-terminal phosphorylation. PDE11A4 expression dramatically increases in the hippocampus with age in the rodent hippocampus, from early postnatal life to late aging, suggesting PDE11A4 function may evolve across the lifespan. Interestingly, PDE11A4 protein shows a 3–10-fold enrichment in the rodent ventral hippocampal formation (VHIPP; a.k.a. anterior in primates) versus dorsal hippocampal formation (DHIPP). Consistent with this enrichment in VHIPP, studies in knockout mice show that PDE11A regulates the formation of social memories and the stabilization of mood and is a critical mechanism by which social experience feeds back to modify the brain and subsequent social behaviors. PDE11A4 likely controls behavior by regulating hippocampal glutamatergic, oxytocin, and cytokine signaling, as well as protein translation. Given its unique tissue distribution and relatively selective effects on behavior, PDE11A may represent a novel therapeutic target for neuropsychiatric, neurodevelopmental, or age-related disorders. Therapeutically targeting PDE11A4 may be a way to selectively restore aberrant cyclic nucleotide signaling in the hippocampal formation while leaving the rest of the brain and periphery untouched, thus, relieving deficits while avoiding unwanted side effects.

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Phosphodiesterase 11: a brief review of structure, expression and function

Cited by 55 publications

References 30 publications

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

The recent phosphodiesterase type 5 inhibitors

A Role for Phosphodiesterase 11A (PDE11A) in the Formation of Social Memories and the Stabilization of Mood

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