Nitric Oxide Activates Trp Channels By Cysteine S-nitrosylation

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.