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isoforms and splice variants. The PDEs differ in their structures, distribution,
modes of regulation, and sensitivity to inhibitors. Since PDEs have been shown
to play distinct roles in processes of emotion and related learning and memory
processes, selective PDE inhibitors, by preventing the breakdown of cAMP and/or
cGMP, modulate mood and related cognitive activity. This review discusses the
current state and future development in the burgeoning field of PDEs in the central
nervous system. It is becoming increasingly clear that PDE inhibitors have thera-
peutic potential for the treatment of neuropsychiatric disorders involving distur-
bances of mood, emotion, and cognition.
Keywords Anxiety
cAMP
cGMP
Cognition
Depression
Phosphodiesterases
Schizophrenia
1
Introduction
Phosphodiesterases (PDEs) are the only known enzymes that catalyze the hydrolysis
of cyclic AMP (cAMP) and cyclic GMP (cGMP) and thus are integral to the
regulation of cyclic nucleotide signaling and cellular communication. PDEs are
encoded by 21 genes and are functionally separated into 11 families, which are
differently expressed in various tissues throughout the body, including the brain
(Conti and Beavo 2007 ; Lugnier 2006 ). PDE families are divided into three cate-
gories based on their substrate specificity: PDE 4, 7, and 8 hydrolyze cAMP; PDE 5,
6, and 9 hydrolyze cGMP; and PDE 1, 2, 3, 10, and 11 are dual substrate enzymes
and hydrolyze both cAMP and cGMP. The PDEs can also be classified by the
mechanisms regulating their activity, such as regulation by cGMP or Ca 2+ /calmod-
ulin, or their N-terminal regulatory domains, such as specific protein-binding
regions, phosphorylation sites, and GAF domains. Current studies indicate that
there are more than 100 different protein products transcribed from the PDEs
genes because of alternative transcriptional start sites and alternative splicing of
gene products (Lugnier 2006 ; Bender and Beavo 2006 ; Menniti et al. 2006 ). The
multiplicity of the PDE gene family and the complex expression patterns of the
different PDEs have raised questions regarding the physiological and pathological
relevance of the multiple isoforms of these enzymes. Various PDEs have been
shown to be involved in intracellular signaling pathways associated with neuropsy-
chiatric disorders or their treatment (O'Donnell and Zhang 2004 ; Kelly and Brandon
2009 ; Millar et al. 2007 ; Schmidt 2010 ; Siuciak 2008 ; Zhang 2009 ). Inhibitors of at
least seven PDEs families have been implicated in behavioral changes related to
cognition, depression, and anxiety, namely those for PDE 1, 2, 4, 5, 9, 10, and 11. In
this review, we provide an overview of the PDE gene superfamily and the effect of
specific PDE inhibitors on intracellular signaling with a particular focus on mood
and cognitive disorders.
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