Biology Reference
In-Depth Information
4 Regulation of Signaling Pathways Involved in Mood
and Cognition by PDE Inhibitors
Cyclic AMP and cGMP, as two critical second messengers, play an important role
in regulating CNS functions, including emotion-related learning and memory, and
nerve growth regeneration (Houslay et al.
2005
; Tanis and Duman
2007
; Teng and
Tang
2006
). The changes in cAMP and cGMP levels are caused by both accumula-
tion resulting from the synthetic cyclases and degradation, which is regulated by
PDEs (Conti et al.
1995
). Actually, the manipulation of cAMP/cGMP degradation
and creation of different local cyclic nucleotide concentrations for selective actions
seem to play a more important role, which makes PDEs promising drug targets
(Bender and Beavo
2006
). There is also ample evidence that cyclic nucleotides are
involved in LTP, since enhanced cAMP/cGMP concentrations can improve LTP
and increase synaptic plasticity; this suggests a potential mechanism for the use of
PDE inhibitors to treat memory dysfunctions (Impey et al.
1996
; Frey et al.
1993
;
Monfort et al.
2004
; Bon and Garthwaite
2003
). Since PDEs are widely distributed
in brain and are key enzymes in the complex cAMP/cGMP regulatory systems
that transduce membrane signals to the nucleus to regulate gene expression, they
have the potential to effect long-term changes in neuronal function. Therefore,
PDEs have become interesting targets in psychiatric and neurological disorders
(Esposito et al.
2009
); the exception to this is PDE6, which is localized to the retina
(Taylor et al.
2001
). In addition, it has been suggested that drugs that target
second messengers might have higher efficacy since they can modulate multiple
biochemical pathways (Blokland et al.
2006
).
4.1 PDE Inhibitors and the cAMP-PKA Pathway
Cyclic AMP, through activating cAMP-dependent protein kinase, can stimulate
the transcription factor CREB, which regulates the transcription of many genes,
such as brain-derived neurotrophic factor (BDNF); this cascade has been suggested
to be involved in the pathophysiology of mood and cognitive disorders (Lonze and
Ginty
2002
). Evidence is accumulating that PDE inhibitors modulate the activity of
cAMP/cGMP-mediated signaling pathways and thus regulate CREB phosphoryla-
tion and the downstream effectors (Reneerkens et al.
2009
). The phosphorylation
of CREB at Ser-133 is required for CREB activation that has been implicated in
plasticity of synaptic function that is important in memory and cognition (Lonze
and Ginty
2002
). Dominant-negative CREB mutation or key CREB isoforms
deletions can affect memory formation and long-term synaptic changes in mice
(Chen et al.
2003
). Moreover, CREB affects the transcription of many critical
genes, such as BDNF, which is a major neurotrophin in the brain and has been
shown to be involved in etiology of depression and actions of antidepressants
(Duman et al.
1999
; Egan et al.
2003
; Sklar et al.
2002
). Decreased phosphorylated
