Biology Reference
In-Depth Information
reported that NMDA receptor activation, which activates MAPK, is required for
LTP induction (Miyamoto
2006
). Moreover, the specific NMDA receptor antago-
nist AP5 inhibits the effect of rolipram on LTP (Navakkode et al.
2005
). This result
is consistent with the report that rolipram reverses the memory deficits induced by
the NMDA receptor antagonist MK-801 (Zhang et al.
2000
,
2005
), suggesting that
PDE4 inhibitors might trigger the NMDA receptor-mediated MAPK/ERK cascade,
and thus phosphorylate CREB (Valera et al.
2008
). However, depending on which
isoforms of Raf are present and to what pools of ERK they interact with (Schaak
et al.
2000
), cAMP can also activate ERK through stimulation of B-Raf (Obara
et al.
2009
), while PKA-mediated phosphorylation of C-Raf inhibits its functioning
and thus ERK activation (Dumaz and Marais
2003
). Indeed, PDE4 inhibitors have
been shown to inhibit the MAPK signaling pathway, which is probably due to PKA-
mediated inhibition of Raf-1 activity (Matousovic et al.
1995
). Therefore, PDEs
inhibitors might regulate MAPK-ERK-CREB signaling via cAMP and indirectly by
altering NMDA receptor function.
Additionally, there is also crosstalk between the ERK and cAMP pathways as
ERK can phosphorylate a conserved serine within the PDE4 catalytic site, whereby
it activates short forms and inhibits long isoforms, providing either positive or
negative interactions dependent upon the target PDE4 isoform (Baillie et al.
2000
;
Mackenzie et al.
2000
).
4.3 PDE Inhibitors and the NO/cGMP/PKG Pathway
Nitric oxide plays an important role in LTP; inhibition of nitric acid synthase (NOS)
reduces LTP significantly (Doyle et al.
1996
; Haley et al.
1993
). cGMP is a
downstream effector of nitric oxide (NO); stimulation of NMDA receptors by
glutamate results in an increase in intracellular calcium, which activates NOS and
leads to enhanced production of NO and activation of soluble guanylyl cyclase
(sGC), which catalyzes cGMP synthesis (Monfort et al. 2004).
There is substantial evidence showing important functions of cGMP-specific
PDEs in memory and synaptic plasticity (Blokland et al.
2006
; Menniti et al.
2007
).
Inhibition of the breakdown of cGMP by PDE5 inhibitors facilitates memory
consolidation in the rodent novel object recognition task (Prickaerts et al.
2002
,
2004
). It has been demonstrated that the PDE5 inhibitor zaprinast increases the
NO-activated cGMP response in the hippocampus (De Vente et al.
1996
; Van
Staveren et al.
2001
), which suggests that the memory-enhancing effect of PDE5
inhibitors might be mediated through NO-cGMP signaling. Prickaerts and cow-
orkers (
2002
,
2004
) have shown that cGMP/PKG pathway is mainly involved in
presynaptic changes and in the early phase of the signaling pathway activated by
PDE5 inhibitors.
It is known that neurogenesis plays a role in synaptic plasticity, memory, and
mood disorders (Bruel-Jungerman et al.
2006
,
2007
). Some studies also show that
treatment of mood disorders such as depression is related to neurogenesis and
synaptic plasticity (Paizanis et al.
2007
). Zhang et al. showed that PDE5 inhibitors
