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KMID : 0811720070110000092
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Korean Journal of Physiology & Pharmacology
2007 Volume.11 No. 0 p.92 ~ p.0
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Identification of Subdomains in NADPH Oxidase-4 (Nox-4) Critical for the Oxygen-dependent Regulation of TASK-1 K+ Channels
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Park Su-Jung
Kim Sung-Joon
Chun Yang-Sook
Park Jong-Wan
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Abstract
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The hypoxia-induced inhibition of K+ channel (e.g. TASK) has been suggested as a critical mechanism of acute responses to hypoxia in various tissues (e.g. pulmonary neuroepithelial body and pulmonary arterial smooth muscle). TASK-1 is a class of tandem-pore K+ channel family and inhibited by hypoxia, and this response is dependent upon the coexpression of NADPH-oxidase 4 (NOX-4), indicating that NOX-4 might be the ‘oxygen sensor’ in the TASK-1/NOX-4 system. However, which part of NOX-4 is responsible for the oxygen sensing remains unknown. In the present study, we examined whether the hypoxia (5% O2)-inhibition of TASK-1/NOX-4 is affected by the coexpression of various deletion mutant forms of NOX-4; Heme-binding domain deletion (HBD(-)), NADPH-binding domain deletion (NBD(-)), FADH-binding domain deletion (FBD(-)), and double mutants for Heme-binding and FADH-binding domains (HFBD(-)). The extent of hypoxia-inhibition of TASK-1 (decrease by 46%) was attenuated to 27 and 26 % by in HBD(-) and FADH(-), respectively. In HFBD(-), the hypoxia inhibited TASK-1 current only by 19 %, which was similar with the response of TASK-1 alone to hypoxia. Also, NBD(-) did not alter the hypoxia-induced inhibition of TASK-1 current. The hypoxia-inhibition of TASK-1 was largely suppressed by heme synthase inhibitor, succinyl acetone. Interestingly, a pretreatment with carbon monoxide (CO, 1%) largely abolished the hypoxia-inhibition of TASK-1, suggesting that heme moiety is a critical component for the oxygen-sensing in TASK-1/NOX-4 expression system. Finally, we found that the coexpression of p22, a partner protein of NOX-4, is required for the hypoxia-inhibition of TASK-1. The above results suggest that the enzymatic action NOX-4 does not play a role in the hypoxia-inhibition of TASK-1. In contrast, a conformational change of NOX-4 by O2-binding to heme-containing domain is critical for the oxygen sensing. The precise roles of FADH-binding domain and p22 remain to be investigated.
Source: Korean Journal of Physiology & Pharmacology.2007 Oct;11(Suppl II):S84-S84
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KEYWORD
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Hypoxia, TASK channel, Oxygen sensing, NADPH oxidase, Heme
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