S2-2 Identification of hydrogen sulfide “receptors” in the receptor tyrosine kinase family and ion channels

One of the most challenging questions in H2S would be identification of the “receptors” for H2S. We identified a new disulfide bond (Cys1045-Cys1024) within the intracellular domain of VEGFR2. H2S cleaved the disulfide bond, activated VEGFR2 and induced angiogenesis. Since the receptor tyrosine kinase family have a conserved intracellular kinase domain though they have different extracellular domains for various extracellular ligands. The second “receptor” we identified in this family is the insulin receptor. We found that H2S directly activated the insulin receptor and promoted glucose up take in both myotubes and adipocytes. Chronic H2S treatment decreased fasting glucose, increased insulin sensitivity and increased glucose tolerance. The third “receptor” we identified in this family is EGFR. In renal tubular epithelial cells, H2S targeted at a disulfide bond related with the Cys797/Cys798 residue of EGFR to induce endocytosis and inhibition of Na+/K+-ATPase via the EGFR/gab1/PI3K/Akt signaling pathway. H2S treatment increased sodium excretion and decreased blood pressure in chronic salt loaded rats. In addition to the receptor tyrosine kinase family, the ion channels may also contain some disulfide bond molecular switch for H2S regulation. We found that H2S directly targeted at the Ito potassium channels in the cardiomyocytes and thereby exerted a potent regularizing effect against fatal arrhythmia in acute myocardial infarction.