[No authors listed]
The slowly activating delayed rectifier K+ current (IKs) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates IKs through the protein kinase C pathway, but the related results are controversial. This study was designed to identify isoenzymes involved in the regulation of IKs by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record IKs in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited IKs in a concentration-dependent manner in native cardiomyocytes. A broad duanyu1531 inhibitor Gö6983 (not inhibiting and a selective inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by peptide inhibitor εV1-2. However, direct activation of duanyu1531 by phorbol 12-myristate 13-acetate (PMA) increased the cloned human IKs in HEK293 cells. Similarly, the cduanyu1531 peptide activator significantly enhanced the current. In contrast, the peptide activator inhibited the current. Further evidence showed that duanyu1531ε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of and attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that duanyu1531ε isoenzyme mediates the inhibitory action of Ang II on IKs and by phosphorylating distinct sites in KCNQ1/KCNE1, cduanyu1531 and duanyu1531ε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism underlying the modulation of the KCNQ1/KCNE1 channel.
KEYWORDS: {{ getKeywords(articleDetailText.words) }}
Sample name | Organism | Experiment title | Sample type | Library instrument | Attributes | |||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
{{attr}} | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
{{ dataList.sampleTitle }} | {{ dataList.organism }} | {{ dataList.expermentTitle }} | {{ dataList.sampleType }} | {{ dataList.libraryInstrument }} | {{ showAttributeName(index,attr,dataList.attributes) }} |
{{ list.authorName }} {{ list.authorName }} |