Biomedical Engineering Reference
In-Depth Information
3.4.2 Protein Kinase C
A possible role for PKC in myogenic signaling was initially suggested on the basis
of inhibitor studies where pharmacological blockade was shown to attenuate
myogenic constriction [
92
,
93
]. A number of these studies were however limited by
the selectivity of the available inhibitors (many of which target the ATP binding site
of the kinase), an inability to distinguish between the multiple PKC isoforms, a lack
of knowledge of the targets for phosphorylation and the pleiotropic actions of the
kinase. For example, with respect to the multiple actions of PKC it has also been
shown to activate membrane channels (for example, VGCC, TrpC isoforms, BK
Ca
)
and other kinases (e.g. p42/44 MAP kinase) both of which could impact contractile
function. More specific support, however, has been given to a possible role for
PKCa which has been demonstrated to translocate to the plasma membrane (con-
sistent with activation) in response to an increase in arteriolar pressure [
94
]. Further,
isozyme-specific inhibition of PKCa attenuates myogenic reactivity [
94
].
The finding that PKC modulates Ca
2+
sensitization through the activation of
CPI-17 and inhibition of MYPT1 provided another possible role for the enzyme in
myogenic signaling. Consistent with this, direct activation of PKC in permeabi-
lized cannulated mesenteric arteries results in increased MLC
20
phosphorylation
despite fixed intracellular Ca
2+
levels [
95
]. However, using a sensitive western
blotting technique Cole and colleagues [
88
,
90
] have been unable to detect pres-
sure-induced changes in CPI-17 phosphorylation in either cerebral or cremaster
muscle small arteries.
3.4.3 Sphingosine Kinase
Membrane sphingomyelin-derived sphingosine has been demonstrated to be
phosphorylated in a number of cell types to sphingosine-1-phosphate (S-1P) and
act as a second messenger acting via receptors coupled to G proteins, PLC and Rho
kinase. Bolz and colleagues have implicated S-1P in myogenic constriction on the
basis that it is activated by depolarization and subsequently stimulates both SR
Ca
2+
release and Rho A-mediated Ca
2+
sensitization. Over expression of sphin-
gosine kinase in isolated gracilis muscle arterioles enhanced myogenic reactivity
via a Rho A-mediated Ca
2+
sensitization while a dominant negative construct
prevented myogenic constriction [
96
]. A current difficulty in understanding the
exact role of S-1P is that it is has also been reported to be involved in contractile
responses to agonists [
97
] suggesting it may not be specific to myogenic con-
tractility. Further, its function is complicated as it appears to exert actions on both
smooth muscle and endothelial cells as well as acting both extracellularly and
intracellularly [
97
]. However, it is interesting to note that alterations in both
myogenic tone and S-1P signaling have been reported in heart failure [
98
].
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