Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of psychosis

Siuciak, Judith A.; Chapin, Douglas S.; Harms, John F.; Lebel, Lorraine A.; McCarthy, Sheryl A.; Chambers, Leslie K.; Shrikhande, Alka; Wong, Sharon; Menniti, Frank S.; Schmidt, Christopher J.

doi:10.1016/j.neuropharm.2006.04.013

Cited by 264 publications

(262 citation statements)

References 45 publications

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“…Furthermore, PDE4 inhibitors improve sensorimotor gating, strengthen memory, and reduce depressive-related behaviors in rodents (e.g., [17][18][19][20][21][22][23]. The PDE10A family has also received much attention in recent years, particularly in the context of schizophrenia because genetic deletion or inhibition of PDE10A results in antipsychotic-like effects in rodents (24)(25)(26). Deletion or inhibition of PDE1, -2, and -5 have also been shown to affect behavior and cognition (27)(28)(29), and up-regulation of PDE1 has been shown in a mouse model of schizophrenia (30).…”

Section: Pde11a Ko Mice Show a Subset Of Phenotypes Associated Withmentioning

confidence: 99%

“…If PDE11A is expressed only in a subpopulation of cells within a discrete subregion of the brain, one might not expect to detect expression when analyzing samples prepared from an entire brain (region). Evidence implicating other PDE families in brain function and psychiatric disease (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), along with a recent report linking PDE11A to major depressive disorder and antidepressant response (31), suggest that it is important to understand the role of PDE11A in the brain. Using in situ hybridization, quantitative real-time PCR, and Western blot, we clarify here where in the brain PDE11A is expressed and, by using PDE11A-deleted mice, we demonstrate a role for PDE11A in brain function.…”

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confidence: 99%

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Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Kelly

Logue

Brennan

et al. 2010

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

156

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Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A −/− knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a twoto threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatricdisease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate α-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (γ2) and γ8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.

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Section: Pde11a Ko Mice Show a Subset Of Phenotypes Associated Withmentioning

confidence: 99%

mentioning

confidence: 99%

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Kelly

Logue

Brennan

et al. 2010

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

156

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“…PDE10A-deficient mice show reduced exploratory behavior when placed in a novel environment and have a blunted response to the psychomotor activating effects of N-methyl-D-aspartate receptor (NMDA) receptor antagonists phencyclidine and MK-801 (15,16). Selective PDE10A inhibitors decrease psychomotor activity, reverse deficits in prepulse inhibition, and inhibit conditioned avoidance responding in rodents, models that are predictive of antipsychotic activity in the clinic (17)(18)(19)(20)(21).…”

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confidence: 99%

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

et al. 2013

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Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

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“…Knockout mice experiments suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation (19). The PDE10 inhibitor papaverine is effective in improving executive function deficits associated with schizophrenia, and therefore inhibition of PDE10 may represent an approach to treatment of psychosis (20,21).PDE families contain a variable N-terminal regulatory domain and a conserved C-terminal catalytic domain. Individual PDE families show different substrate preferences.…”

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confidence: 99%

Structural insight into substrate specificity of phosphodiesterase 10

Wang

Liu

Hou

et al. 2007

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

103

139

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Phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. It remains unknown how individual PDE families selectively recognize cAMP and cGMP. This work reports structural studies on substrate specificity. The crystal structures of the catalytic domains of the D674A and D564N mutants of PDE10A2 in complex with cAMP and cGMP reveal that two substrates bind to the active site with the same syn configuration but different orientations and interactions. The products AMP and GMP bind PDE10A2 with the anti configuration and interact with both divalent metals, in contrast to no direct contact of the substrates. The structures suggest that the syn configurations of cAMP and cGMP are the genuine substrates for PDE10 and the specificity is achieved through the different interactions and conformations of the substrates. The PDE10A2 structures also show that the conformation of the invariant glutamine is locked by two hydrogen bonds and is unlikely to switch for substrate recognition. Sequence alignment shows a potential pocket, in which variation of amino acids across PDE families defines the size and shape of the pocket and thus determines the substrate specificity.crystal structure ͉ cyclic nucleotides cAMP and cGMP C yclic nucleotide phosphodiesterases (PDEs) are enzymes hydrolyzing the second messengers adenosine and guanosine 3Ј,5Ј-cyclic monophosphates (cAMP and cGMP). The human genome encodes 21 PDE genes that are categorized into 11 families (1, 2). Selective inhibitors against individual PDE families have been developed as therapeutics for treatment of various human diseases (3-8). The best known examples are the PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) that have been used for treatment of male erectile dysfunction (5). Sildenafil (Revatio) has also been approved for treatment of pulmonary hypertension (9). PDE10 was independently identified by three groups in 1999 and shows a dual activity on hydrolysis of both cAMP and cGMP (10-12). PDE10 is highly expressed in brain striatum (13-16). Reduction of PDE10A mRNA and protein levels in striatum of transgenic mice implies a role of PDE10A in Huntington's disease (17,18). Knockout mice experiments suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation (19). The PDE10 inhibitor papaverine is effective in improving executive function deficits associated with schizophrenia, and therefore inhibition of PDE10 may represent an approach to treatment of psychosis (20,21).PDE families contain a variable N-terminal regulatory domain and a conserved C-terminal catalytic domain. Individual PDE families show different substrate preferences. Crystal structures have been reported for the catalytic domains of seven PDE families in the unliganded form or in complex with inhibitors or products: PDE1B, PDE2A, PDE3B, PDE4B/4D, PDE5A, PDE7A, and PDE9A (22-34). However, it remains a puzzle how the conserved catalytic pocket of the PDE famili...

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Inhibition of the striatum-enriched phosphodiesterase PDE10A: A novel approach to the treatment of psychosis

Cited by 264 publications

References 45 publications

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Genetic Deletion and Pharmacological Inhibition of Phosphodiesterase 10A Protects Mice From Diet-Induced Obesity and Insulin Resistance

Structural insight into substrate specificity of phosphodiesterase 10

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