Biology Reference
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present at high levels in human myocardium, as an alternative target for inotropic
and cardioprotective actions.
Keywords cAMP
Cardiomyopathy
Cardioprotection
cGMP
Inotropy
PDE1
PDE3
PDE5
PDE4
1 PDE3 Cyclic Nucleotide Phosphodiesterases in Human
Myocardium
PDE3 isoforms constitute the majority of the membrane-associated cAMP-hydrolytic
activity and a large fraction of the cytosolic cAMP-hydrolytic activity in human
myocardium (Hambleton et al.
2005
;Vandeputetal.
2007
). These enzymes are
dual-specificity enzymes, hydrolyzing both cAMP and cGMP with high affinities
(
K
m
~0.1
m
M). Their catalytic rates for cAMP are much higher than their catalytic
rates for cGMP; for this reason, they have generally been thought of primarily as
cGMP-inhibited cAMP phosphodiesterases. Inhibition of the cAMP-hydrolytic activ-
ity of PDE3 by cGMP has been shown to be involved in its regulation of delayed-
rectifier K
+
currents and L-type Ca
2+
currents in cardiac myocytes (Shimizu et al.
2002
; Frace et al.
1993
; Vandecasteele et al.
2001
), and there is evidence that cGMP
may have inotropic effects in hypertrophic right ventricular myocardium that result
from PDE3 inhibition (Nagendran et al.
2007
). It should be noted, however, that
the cGMP-hydrolytic activity of PDE3 comprises a significant fraction of the cGMP-
hydrolytic activity recovered in soluble (cytosolic) and particulate (membrane-
derived) fractions of human myocardium (Vandeput et al.
2007
,
2009
)(Fig.
1
),
and the possible role of these enzymes as cGMP phosphodiesterases has, to our
knowledge, not been explored.
Within the PDE3 family, two genes - PDE3A and PDE3B - have been identified.
Most of the PDE3 activity in cardiac myocytes appears to consist of three isoforms -
PDE3A1, PDE3A2, and PDE3A3 - that appear to be generated from the
PDE3A
gene through transcription and translation from alternative start sites (Fig.
2
)
(Wechsler et al.
2002
; Choi et al.
2001
). As a result, the amino acid sequences of
these isoforms are identical except for differences in the lengths of N-terminal
sequence that are included. PDE3A1, the longest isoform, has thus far been found
only in cardiac myocytes and oocytes; in the former, this isoform is recovered
exclusively in membrane-derived particulate fractions (Han et al.
2006
). PDE3A1
contains two membrane-localizing domains: “NHR1”, which consists of hydropho-
bic loops that insert into intracellular membranes, and “NHR2”, which appears to
be important in protein-protein interactions (Kenan et al.
2000
; Shakur et al.
2000
).
PDE3A1 also contains three sites - P1 (S293/S294), P2 (S312), and P3 (S428) -
that are phosphorylated, with overlapping specificities, by PKA, PKB, and PKC.
Two shorter isoforms, PDE3A2 and PDE3A3, are recovered in cytosolic as well
as membrane-derived and fractions. PDE3A2 lacks NHR1 and the upstream
phosphorylation site, while PDE3A3 lacks NHR1, NHR2, and the three phosphory-
lation sites. The three isoforms all contain the C-terminal catalytic region (CCR),
