Biology Reference
In-Depth Information
roles for PDE2 and PDE3 in regulating endothelial function. Until recently, PDE4
inhibition was thought to improve endothelial barrier function via increased
cAMP/PKA levels in the cell (Suttorp et al.
1993
). However, other data have
demonstrated that in some circumstances increased cAMP in the cytosol can
cause increased endothelial permeability (Sayner et al.
2004
,
2006
). Recently, it
was demonstrated that PDE4D4 is responsible for containing cAMP to a membrane
pool, restricting cAMP access to the cytosol where it can lead to increased perme-
ability (Creighton et al.
2008
). These findings demonstrate the complexity of cyclic
nucleotide signaling in the control of endothelial permeability and the critical role
of PDEs in regulating this important function.
8 Crosstalk Between cGMP and cAMP: The Role of PDEs
The findings that cGMP can regulate cAMP hydrolysis by both PDE2 and PDE3 to
alter cAMP levels are in agreement with previous work demonstrating a barrier-
enhancing effect of cAMP and further our understanding of the regulation of cAMP
in endothelial cells (Surapisitchat et al.
2007
). At low concentrations, cGMP can
regulate cAMP-mediated enhancement of barrier function via inhibition of PDE3,
but, at higher cGMP concentrations, via activation of PDE2, it can mediate break-
down of barrier function. These results are some of the few in which the same pool
of cGMP has been shown to both inhibit PDE3 and activate PDE2 to regulate the
same cellular function. For example, in human atrial myocytes, cGMP can regulate
L-type Ca
2+
channel current by modulating cAMP and PKA via PDE2 and PDE3
(Vandecasteele et al.
2001
). The functional effect of cGMP is concentration-
dependent since the IC
50
of cGMP for PDE3A is nearly 20-fold less than
the EC
50
for activation of PDE2 (Leroy et al.
1996
; Surapisitchat et al.
2007
;
Yamamoto et al.
1983
). This difference correlates well with normal versus patho-
logical levels of guanylyl cyclase agonists such as ANP and NO. In healthy
individuals, these agonists are relatively low, resulting in low levels of cGMP
leading to inhibition of PDE3A, increased cAMP, and enhanced barrier function.
Under several pathological conditions such as heart failure and inflammation, ANP
and NO increase significantly leading to greatly increased cGMP levels, activation
of PDE2A, decreased cAMP levels, and thus decreased barrier function. In addition
under some pathological conditions, the relative expression of PDEs can be altered.
For example, TNF-
a
, an inflammatory cytokine, induces PDE2 and decreases
PDE3 expression, thereby altering the cellular responses to cGMP signaling
(Seybold et al.
2005
; Surapisitchat et al.
2007
). Thus, PDE2 and PDE3 in the
endothelium may act as sensors or switches to detect normal versus pathological
concentrations of cGMP and thus regulate endothelial permeability accordingly.
Furthermore, the relative expression of these PDEs controls the sensitivity of this
switch to cGMP.
