Mechanotransduction and the Myogenic Response in Diabetes - The Mechanobiology of Obesity and Related Diseases - page 232

Stretch-activated channels (SACs), for which gating is modulated by physiological
levels of stretch, have been demonstrated in a variety of tissues including smooth
muscle cells from porcine coronary arteries [ 28 ]. The opening of these SACs has
been shown to result in a dominant Na + current that leads to membrane depolar-
ization [ 28 , 32 ]. Membrane stretch also activates BK Ca channels [ 31 ], producing a
hyperpolarizing current that may limit the extent of depolarization and, hence, in
the intact vessel, myogenic constriction; this conceivably serves as an important
negative feedback mechanism to limit the effects of additional myogenic con-
traction resulting from pressure-induced vasoconstriction of downstream arterioles.
The lack of specific tools to examine the roles of SAC in the myogenic response (for
example, Gd 3+ blocks both SACs and VGCC) coupled with our currently incom-
plete understanding of the molecular identity and regulation of SACs makes it
difficult to appreciate and delineate the specific roles of their activation during
myogenic contraction.
Trp channels represent a diverse family of cation channels that have been
implicated in a variety of sensory events including mechanosensation and
responsiveness to changes in temperature and osmolality [ 33 , 34 ]. Trp proteins are
also implicated in store depletion-mediated Ca 2+ entry and receptor activation
[ 34 ]. Of potential importance to myogenic signaling, these channels exhibit a
spectrum of permeability characteristics from that of NSCCs to some that show a
high Ca 2+ selectivity. In mammals approximately 30 Trp channel genes give rise
to a number of sub-families, which have been designated canonical (TrpC; 7
members); vanilloid (TrpV; 6 members) and melastatin (TrpM; eight members). In
addition, related sub-families are the mucolipins, TrpML; polycystins, TrpP; and
ankyrin, TrpA. Division into these sub-families is based on amino acid sequence
homology. For the main classes of Trp proteins the variation in sequence is most
evident in the intracellularly located N- and C-terminal domains.
The active channel exists as a tetramer and evidence points towards both homo-
and extensive hetero-multimerization. The latter observation potentially poses
difficulties when interpreting the results from expression systems where the for-
mation of homo-multimerization is generally the case [ 35 ]. Further complexity
may also arise given that recent reports suggest that cross-talk may occur between
various Trp channels and that this may, in part, be dependent on agonist con-
centration [ 34 , 36 ] or, in the case of myogenic responsiveness, the degree of
mechanical stimulation. This latter point may relate to the fact that various Trp
channels are, themselves, regulated by signaling molecules including Ca 2+ , diac-
ylglycerol (DAG) and protein kinase C (PKC).
Initial interest in Trp channel activation in myogenic signaling was provided by
the studies of Welsh et al. (2002) who used in vitro anti-sense oligonucleotide
knockdown approaches to examine the role of TrpC6 in isolated cerebral small
arteries. Decreased expression of TrpC6 resulted in marked attenuation of both
pressure-induced depolarization and myogenic constriction. Further, the oligonu-
cleotide treatment decreased the activation of cation channels in isolated cerebral
artery SMCs in response to a hyper-osmotic challenge. Earley and colleagues
[ 34 , 35 ] later demonstrated that oligonuceotide knockdown of TrpM4 expression