A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism.
A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of KV4.2 channels by a pore-blocking mechanism.
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DOI：
10.4161/chan.3.6.10216
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Pfaffinger PJ
中科院分区：
文献类型：
--
作者：
Jerng HH;Dougherty K;Covarrubias M;Pfaffinger PJ
The somatodendritic subthreshold A-type K+ current in neurons (ISA) depends on its kinetic and voltage-dependent properties to regulate membrane excitability, action potential repetitive firing, and signal integration. Key functional properties of the Kv4 channel complex underlying ISA are determined by dipeptidyl peptidase-like proteins known as dipeptidyl peptidase 6 (DPP6) and dipeptidyl peptidase 10 (DPP10). Among the multiple known DPP10 isoforms with alternative N-terminal sequences, DPP10a confers exceptionally fast inactivation to Kv4.2 channels. To elucidate the molecular basis of this fast inactivation, we investigated the structure-function relationship of the DPP10a N-terminal region and its interaction with the Kv4.2 channel. Here, we show that DPP10a shares a conserved N-terminal sequence (MNQTA) with DPP6a (aka DPP6-E), which also induces fast inactivation. Deletion of the NQTA sequence in DPP10a eliminates this dramatic fast inactivation, and perfusion of MNQTA peptide to the cytoplasmic face of inside-out patches inhibits the Kv4.2 current. DPP10a-induced fast inactivation exhibits competitive interactions with internally applied tetraethylammonium (TEA), and elevating the external K+ concentration accelerates recovery from DPP10a-mediated fast inactivation. These results suggest that fast inactivation induced by DPP10a or DPP6a is mediated by a common N-terminal inactivation motif via a pore-blocking mechanism. This mechanism may offer an attractive target for novel pharmacological interventions directed at impairing ISA inactivation and reducing neuronal excitability.
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影响因子：
3.5
作者：
Jerng, Henry H.;Lauver, Aaron D.;Pfaffinger, Paul J.
通讯作者：
Pfaffinger, Paul J.
影响因子：
4.4
作者：
Covarrubias, Manuel;Bhattacharji, Aditya;Wang, Guangyu
通讯作者：
Wang, Guangyu
影响因子：
4.5
作者：
CHAHINE, M;BENNETT, PB;HORN, R
通讯作者：
HORN, R
DOI：
10.1085/jgp.113.5.641
发表时间：
1999-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Jerng HH;Shahidullah M;Covarrubias M
通讯作者：
Covarrubias M
影响因子：
56.9
作者：
HOSHI, T;ZAGOTTA, WN;ALDRICH, RW
通讯作者：
ALDRICH, RW