Biology Reference
In-Depth Information
2 Distribution of PDE Isoforms in the Brain
Studies indicate a high distribution of PDEs in the frontal cortex, hippocampus,
amygdala, olfactory bulb, striatum, hypothalamus, and cerebellum, besides the expres-
sion in numerous other body structures, which are important in modulating emotion,
learning, and memory. Since PDEs are involved in the regulation of second messenger
signaling, their inhibition in the brain has provided valuable insights into the biological
mechanisms that underlie central nervous system (CNS) disorders and the discovery of
mood and cognitive modulators.
PDE1 consists of three different subtypes, 1A, 1B, and 1C, which can be found
in the human brain at the level of hippocampus and cerebral cortex, suggesting that
this enzyme may play a crucial role in memory formation and storage (Deshmukh
et al.
2009
). The high concentrations of PDE1A and PDE1B mRNA expression in
olfactory bulb and striatum indicate their potential function in depression, schizo-
phrenia, and other mental and cognitive illnesses. PDE1C is expressed exclusively
in the olfactory cilia together with adenylyl cyclase III, which are both Ca
2+
-
regulated enzymes and form a point of crosstalk for integrating calcium and
cAMP signaling in these neurons (Juilfs et al.
1997
).
PDE2 is highly expressed in brain limbic structures and adrenal gland (Boess
et al.
2004
; Nikolaev et al.
2005
). The enriched PDE2 expression in the hippo-
campus, cerebral cortex, amygdala, hypothalamus, pituitary, and adrenal cortex
suggests that it may be involved in negative feedback inhibition of the limbic-
hypothalamus-pituitary-adrenal (limbic-HPA) axis in emotion, and learning and
memory processes.
PDE3 is expressed at relatively constant and low levels throughout the brain
(Bolger et al.
1994
).
A high distribution of PDE4 in the hippocampus, frontal cortex, olfactory bulb,
and cerebellum has been reported (Kaulen et al.
1989
; Zhan et al.
2003
; Dlaboga
et al.
2006
; McPhee et al.
2001
). Four PDE4 genes (PDE4A, 4B, 4C, and 4D),
encoding at least 25 splice variants, have been identified (Conti et al.
2003
; Houslay
et al.
2007
; Houslay
2010
). Long-form variants contain two conserved regions
called Upstream Conserved Region 1 (UCR1) and 2 (UCR2), while short isoforms
lack UCR1 (Bolger et al.
1993
). Long isoforms contain a site within UCR1
that confers stimulatory phosphorylation by protein kinase A (Sette et al.
1994
;
MacKenzie et al.
2002
). PDE4 subtypes appear to be involved in different central
functions based on their patterns of distribution in the brain (Cherry and Davis
1999
; Engels et al.
1995
; McPhee et al.
2001
; Mir
´
et al.
2002
;P
´
rez-Torres et al.
2000
; Zhang
2009
). PDE4A and PDE4D are highly expressed in the cerebral
cortex, olfactory bulb, hippocampal formation, and brainstem. PDE4B is highly
expressed in the amygdala, striatum, and hypothalamus, suggesting its possible
role in the mediation or treatment of anxiety and schizophrenia. The side effects of
