Biology Reference
In-Depth Information
and contributes to specificity in intracellular signaling (Conti and Beavo
2007
;
Houslay
2010
).
3.1 PDE1
PDE1 family members are considered dual-substrate enzymes involved in the regu-
lation of both cGMP and cAMP through their degradation (Bender and Beavo
2006
).
In vitro, PDE1A and PDE1B isozymes hydrolyze cGMP with much higher affinity
than cAMP, while the PDE1C isozyme hydrolyzes cAMP and cGMP with equally
high affinity. In vivo, several studies have shown that PDE1A and PDE1B primarily
regulate cGMP (Nagel et al.
2006
; Bender and Beavo
2006
; Miller et al.
2009
), while
PDE1C regulates intracellular cAMP levels in various cell types including neurons
(Rybalkin et al.
2002
; Han et al.
1999
; Dunkern and Hatzelmann
2007
).
PDE1 inhibition has been reported to cause cerebral artery dilation, which can
affect CNS function by elevation of cGMP levels (Kruuse et al.
2001
). The PDE1
inhibitor vinpocetine facilitates long-term potentiation (Molnar and Gaal
1992
),
enhances the structural dynamics of dendritic spines, and improves aversion-related
memory retrieval (DeNoble
1987
). A recent study indicates that vinpocetine treat-
ment of streptozotocin-infused rats improves memory consolidation as evidenced
by increased time spent in the target quadrant in the Morris water maze test
(Deshmukh et al.
2009
). Most recently, Filgueiras and colleagues (
2010
) reported
that vinpocetine improves learning and memory deficits in rats exposed to alcohol.
3.2 PDE2
PDE2 is a 105-kDa homodimer that exists in particulate and soluble forms (Zaccolo
and Movsesian
2007
). It belongs to a family of proteins that regulates the intracel-
lular levels of both cGMP and cAMP. Although cGMP is the preferred substrate
for this enzyme, PDE2 hydrolyzes both cGMP and cAMP with positively coopera-
tive kinetics (Wu et al.
2004
). Therefore, the biological function of PDE2 may, to
some degree, involve interaction between cAMP- and cGMP-mediated signaling
mechanisms (Hajjhussein et al.
2007
).
The distribution of PDE2 in limbic structures, such as hippocampus and amyg-
dala, may suggest a role in emotion and memory operations, such as the formation of
stable declarative (or explicit) memory in humans and spatial (or relational/contex-
tual) memory in rodents. PDE2 is also found in a subset of olfactory neurons, where
its inhibition increases cGMP, stimulates cyclic nucleotide-gated channels to open,
and initiates a depolarizing response (Meyer et al.
2000
). Neuronal projections from
the olfactory bulbs to the limbic system have a major influence on emotional
behaviors involved in depression and anxiety. In addition, depressive symptoms
