Premium
Oxyhemoglobin‐induced Kv current suppression: MMP activation, HB‐EGF shedding and EGFR‐PTK activation
Author(s) -
Koide Masayo,
Wellman George C.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a517-d
Subject(s) - chelerythrine , protein kinase c , chemistry , microbiology and biotechnology , epidermal growth factor , tyrosine kinase , matrix metalloproteinase , signal transduction , receptor , biochemistry , biology
Oxyhemoglobin (OxyHb) causes vasoconstriction through activation of protein tyrosine kinase (PTK) and suppression of voltage‐dependent K + (Kv) channels (Ishiguro et al, Circ Res 2006). Here, we have examined the mechanism linking OxyHb to PTK activation and Kv current suppression. Voltage‐dependent outward K + currents were measured using the conventional patch clamp technique in rabbit cerebral myocytes. OxyHb reduced Kv current by 30 %, which was inhibited by a specific epidermal growth factor receptor (EGFR)‐PTK inhibitor, AG 1478. EGFR‐PTK activation by EGF or heparin binding‐EGF (HB‐EGF) caused Kv current suppression, mimicking the effect of OxyHb. OxyHb‐induced, and EGF‐induced Kv current suppression was still observed in the presence of protein kinase C (PKC) inhibitor (chelerythrine), suggesting this pathway was independent of PKC activity. EGFR ligands exist on the cell surface as precursor proteins that are cleaved by matrix metalloprotease (MMP). Gelatin zymography demonstrated enhanced MMP activity in OxyHb‐treated arteries. MMP inhibitor (GM 6001) and HB‐EGF competitors (heparin or CRM 197) abolished OxyHb‐induced Kv suppression. In conclusion, these data demonstrate OxyHb through MMP activation causes HB‐EGF shedding leading to EGFR‐PTK activation and Kv channel suppression. Supported by the Totman Medical Research Trust Fund and the NIH (R20 RR16435 & R01 HL078983 ).