Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 233

similarly impaired pressure-induced membrane depolarization and vasoconstric-
tion. Reduction of the closely related TrpM5 using a similar approach did not,
however, affect membrane depolarization or subsequent myogenic constriction
suggesting a degree of specificity. The importance of TrpM4 in myogenic sig-
naling was also suggested in vivo as antisense oligonucleotide treatment resulted
in impaired cerebral blood flow autoregulation [ 37 ].
The properties of TrpM4 channels are consistent with a role in myogenic sig-
naling as they are selective for monovalent cations and are activated by both Ca 2+
and PKC. However, TrpM4 is not inherently mechanosensitive suggesting that it's
role must lie downstream of the initial mechanosensory events. Earley suggested
that the mechanosensitive TrpC6 may be positioned upstream in the signaling
pathway providing stretch-induced Ca 2+ entry as an activator of TrpM4. Perhaps
arguing against this, TrpC6-/- genetically-modified mice show enhanced basal
VSMC membrane depolarization and slightly elevated systemic blood pressure
(116 ± 1 vs 123 ± 1 mmHg) as measured by telemetry [ 38 ]. Observations in this
genetic model are possibly complicated by an increased, and presumed compen-
satory, expression of TrpC3 [ 38 ]. In earlier studies, however, a 50 % decrease in
TRPC3 expression using antisense oligonucleotides did not inhibit myogenic
constriction in cerebral arteries [ 39 ]. Interpretation of these apparently conflicting
data may, however, be influenced by redundancy in the roles of various Trp
channels in VSMCs [ 40 ]. Further, expression systems might not effectively
account for post-translational events including trafficking, docking and hetero-
multimerization of functional Trp channels [ 24 ].
TrpC1 was initially reported to be a candidate for being a stretch-sensitive
cation channel [ 41 ]. Specific interest for a role of TrpC1 in vascular smooth
muscle was also supported by the finding that its expression level is relatively high
in this tissue. However, subsequent expression system studies did not demonstrate
mechanosensitivity of homomeric TrpC1 channels [ 42 ]. Further, a role as a spe-
cific myogenic sensor, or component of the pressure-induced depolarization
pathway, was also proved unlikely by the observations that TrpC1-/- genetically-
modified mice have a normal phenotype and unaltered levels of cerebral artery
myogenic tone [ 42 ]. Importantly, the TrpC1 deletion did not alter the expression
levels of the other members of the canonical Trp family. Collectively, these studies
provide little current support for a critical role for TrpC1 in myogenic signaling.
Polycystins (encoded by the PKD1 and PKD2 genes) have been implicated
in polycystic renal disease and have been shown to play a mechanosensory role in
ductal cilia. They have further been shown to mediate Ca 2+ entry and release in
response to fluid flow. At a molecular level, the extracellular region of polycystins
both resembles fibronectin [ 43 ] and has been shown, using single molecule force
spectroscopy, to undergo stretch-induced changes in conformation that restore
when the applied force is removed [ 44 ]. In a recent study, the presence of poly-
cystins in arteriolar smooth muscle has been confirmed and a novel role in
myogenic signaling has been proposed [ 45 ]. Rather than acting as an ion channel,
per se, TrpPP2 has been suggested to be a regulatory molecule for (yet to be
molecularly characterized) stretch activated channels.