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to the Golgi complex (Percival et al.
2010
; Fig.
1
). PKG is also localized to the
neuromuscular junction (Chao et al.
1997
). NO can also act through cGMP-inde-
pendent pathways by directly reacting with thiol residues of cysteine groups. This
NO-based posttranslational modification, known as S-nitrosylation, is also an
important signal transduction mechanism. For example, the activity of skeletal
muscle RyR1, the ryanodine Ca
2+
release channel, is positively regulated by
nitrosylation (Eu et al.
2000
, Fig.
1
). Therefore, in skeletal muscle, nNOS-synthe-
sized NO signals can be propagated through both cGMP-dependent and cGMP-
independent mechanisms.
Rapid modulation of NO-cGMP signaling is mediated both by the rate of cGMP
synthesis and by cGMP degradation by cGMP-PDEs. Several different PDEs are
able to hydrolyze cGMP including PDEs 1, 2, 3, 5, 6, 9, and 11. cGMP-specific
PDEs, such as PDE5A, hydrolyze only cGMP, thereby decreasing the cellular
levels of cGMP (Bender and Beavo
2006
; Fig.
1
). Inhibition of these cGMP-
hydrolyzing PDEs can raise cGMP levels and effectively amplify the upstream
NO signal. One of the most studied cGMP-PDEs is PDE5A, which is predomi-
nantly expressed in the vascular smooth muscle cells (VSMCs) of most vascular
beds, fibroblasts, and myofibroblasts (Wallis et al.
1999
). PDE5A-mediated cGMP
degradation promotes smooth muscle contraction with concomitant blood vessel
constriction. Active PDE5A is also expressed in skeletal muscle homogenates and
cell lines including C2C12 myoblasts and myotubes (Bloom
2002
; unpublished
observations). Although PDE5A expression in cardiomyocytes has been reported,
this issue is contentious since others contend there is no significant PDE5A expres-
sion or activity in these cells (Senzaki et al.
2001
; Takimoto et al.
2005
; Reffelmann
and Kloner
2009
; Lukowski et al.
2010
). Thus, PDE5A is expressed in skeletal and
smooth muscles and perhaps at very low levels in cardiomyocytes. nNOS is also
expressed in VSMCs and cardiomyocytes (Xu et al.
1999
; Ward et al.
2005
).
In VSMCs, nNOS promotes smooth muscle relaxation and blood vessel dilation,
particularly during chronic hypoxia (Ward et al.
2005
). It is clear that skeletal,
cardiac, and smooth muscle cells possess the necessary molecular machinery for
localized nNOS-cGMP signaling (Fig.
1
). Importantly, inhibition of PDE5 activity
provides a general approach to amplify nNOS-mediated signal transduction, or to
broadly enhance NO-cGMP signaling activity, particularly in smooth muscle cells.
Recent studies of NO signaling in skeletal muscle have provided new insights into
nNOS function. nNOS
m
participates in pathways that regulate (1) contraction-induced
glucose uptake and glucose homeostasis, (2) muscle mass and atrophy (3) mito-
chondrial integrity (4) susceptibility to fatigue (5) postexercise strength (6) exag-
gerated exercise-induced inactivity,
(7) and blood delivery during exercise
Fig. 1 (continued) kinase substrate; PKG, protein kinase G (cGK); L-arg, L-arginine; LTCC,
L-type calcium channel; MLCP, myosin light chain phosphatase; NO, nitric oxide; PDE, phos-
phodiesterase; pGD, particulate guanylyl cyclase; PMCA4, plasma membrane calcium ATPase 4;
RGS2, regulator of G protein signaling 2; RyR, ryanodine receptor; sGC, soluble guanylyl cyclase;
SPN, sarcospan; SR, sarcoplasmic reticulum
