Karimi Abdul Ghani

Takashi Yoshida et al.: Nitric oxide activates TRP channels by cysteine

S-nitrosylation
TRP proteins form plasma-membrane cation channels that act as
sensors for diverse cellular stimuli. Here, a novel activation mechanism
mediated by cysteine S-nitrosylation in TRP channels has reported. The
TRPCs and TRPV families induce entry of Ca2+ into cells in response to
nitric oxide (NO).
The author has described cysteine modification as a previously
unknown mechanism that triggers activation gating of TRP channels.
Labeling and functional assays using cysteine mutants together with
membrane sidedness in activating reactive
disulfides show that cytoplasmically
accessible Cys553 and Cys558 are
nitrosylation sites mediating NO sensitivity
in TRPC5. NO activates TRPC5 channels
via sulfhydryl modifications and acts
through cGMP-independent pathways such
as nitrosylation of free sulfhydryl groups of
cysteine residues. NO and reactive
disulfides share a covalent modification site
in TRPC5-channel protein complexes. NO
is a pleiotropic cell signaling molecule that
controls diverse biological processes.
Mo d e l f o r TR P c ha n n e l a c t iva t io n b y N O a n d rea c t ive d i su lf id e s .

The heteromultimeric TRPC5/TRPC1 and TRPC5/TRPC4 channels

are conducting native NO-activated Ca2+ influx in endothelial cells and may
enable TRPC5 to maintain its NO-sensing function while acquiring
resistance to the pathological action of reactive oxygen species. The NO
and reactive disulfides exert their actions independently of receptor-induced
Ca2+ store depletion in activating TRPC5. NO and reactive disulfides
selectively modify Cys553 and Cys558 residues that are coupled to the
gating apparatus in functionally critical domains of the TRPC5 protein. In
fact, Ca2+ entry via SOCs is potentiated indirectly by NO through the
enhancement of Ca2+ release. NOS inhibitor N -nitro-L-arginine
2+
methylester failed to affect Ca release but significantly (P < 0.001)
2+
suppressed the Ca influx and NO production. These finding reveal the
structural motif for the NO-sensitive activation gate in TRP channels and
indicate that NO sensors are a new functional category of cellular receptors
extending over different TRP families.