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Oxyhemoglobin‐induced suppression of KV channels by enhanced tyrosine kinase activity and channel endocytosis
Author(s) -
Wellman George C.,
Ishiguro Masanori,
Morielli Anthony D.,
Tranmer Bruce I,
Penar Paul L.
Publication year - 2006
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.20.5.a1113-a
Subject(s) - endocytosis , chemistry , tyrosine kinase , biophysics , microbiology and biotechnology , biochemistry , biology , signal transduction , cell
Oxyhemoglobin (oxyhb) released following SAH has been implicated in cerebral vasospasm as it causes cerebral artery constriction and increases tyrosine kinase activity. Voltage‐dependent, Ca 2+ ‐selective and K + ‐selective ion channels play an important role in the regulation of cerebral artery diameter and represent potential targets of oxyhb. Here, we demonstrate that acute exposure (10 min) of oxyhb selectively decreases 4‐AP‐sensitive, voltage‐dependent K + channel (K V ) currents by ≈30 % in myocytes isolated from rabbit cerebral arteries, but did not directly alter the activity of voltage‐dependent Ca 2+ channels (VDCCs) or large conductance Ca 2+ ‐activated (BK) channels. A combination of tyrosine kinase inhibitors abolished the ability of oxyhb to decrease K V channel currents. To explore whether oxyhb altered trafficking of K V channels to the plasma membrane, we used an antibody generated against surface K V 1.5 channels. In the presence of oxyhb, staining of surface K V 1.5 was markedly reduced, while staining with the early endosomal marker, EEA‐1, was enhanced. Further, oxyhb caused a loss of spatial distinction between staining with K V 1.5 and the general anti‐phosphotyrosine antibody, PY‐102. We propose that oxyhb‐induced suppression of K V currents occurs via a mechanism involving tyrosine phosphorylation and channel endocytosis. This novel mechanism may contribute to oxyhb‐induced cerebral artery constriction following SAH. Supported by the Totman Medical Research Trust Fund and the NIH (P20 RR16435 & R01 HL078983 ).