Author: Hou, Panpan ; Zhong, Ling ; Cohen, Ira S ; Shi, Jingyi ; Cui, Jianmin ; Zuckerman, Joan ; Gao, Junyuan ; Zhao, Lu ; Wang, Hong Zhan ; Liu, Huilin

AbstractThe cardiac KCNQ1 + KCNE1 (IKs) channel regulates heart rhythm under both normal and stress conditions. Under stress, the β-adrenergic stimulation elevates the intracellular cyclic adenosine monophosphate (cAMP) level, leading to KCNQ1 phosphorylation by protein kinase A and increased IKs, which shortens action potentials to adapt to accelerated heart rate. An impaired response to the β-adrenergic stimulation due to KCNQ1 mutations is associated with the occurrence of a lethal congenital long QT syndrome (type 1, also known as LQT1). However, the underlying mechanism of β-adrenergic stimulation of IKs remains unclear, impeding the development of new therapeutics. Here, we find that the unique properties of KCNQ1 channel gating with two distinct open states are key to this mechanism. KCNQ1's fully activated open (AO) state is more sensitive to cAMP than its intermediate open state. By enhancing the AO state occupancy, the small molecules ML277 and C28 are found to effectively enhance the cAMP sensitivity of the KCNQ1 channel, independent of KCNE1 association. This finding of enhancing AO state occupancy leads to a potential novel strategy to rescue the response of IKs to β-adrenergic stimulation in LQT1 mutants. The success of this approach is demonstrated in cardiac myocytes and also in a high-risk LQT1 mutation. In conclusion, the present study not only uncovers the key role of the AO state in IKs channel phosphorylation, but also provides a target for antiarrhythmic strategy.

13 Sep 2024·Circulation Research

Targeting the I _Ks Channel PKA Phosphorylation Axis to Restore Its Function in High-Risk LQT1 Variants

Article

Author: Yao, Jing ; Hou, Panpan ; Zhu, Wandi ; Huang, Chen ; Wang, Changhe ; Neher, Erwin ; Jiang, Dexiang ; Kang, Xinjiang ; Xiao, Chenxin ; Jiang, Zhi-Hong ; Lin, Xiaoqing ; Yang, Huaiyu ; Weng, Kuo-Chan ; Shen, Bing ; Chung, Sookja Kim ; Silva, Jonathan R. ; Ouyang, Yue ; Zhong, Ling ; Yan, Zhenzhen ; Zhang, Hangyu

BACKGROUND: The KCNQ1+KCNE1 (I Ks ) potassium channel plays a crucial role in cardiac adaptation to stress, in which β-adrenergic stimulation phosphorylates the I Ks channel through the cyclic adenosine monophosphate (cAMP)/PKA (protein kinase A) pathway. Phosphorylation increases the channel current and accelerates repolarization to adapt to an increased heart rate. Variants in KCNQ1 can cause long-QT syndrome type 1 (LQT1), and those with defective cAMP effects predispose patients to the highest risk of cardiac arrest and sudden death. However, the molecular connection between I Ks channel phosphorylation and channel function, as well as why high-risk LQT1 mutations lose cAMP sensitivity, remain unclear. METHODS: Regular patch clamp and voltage clamp fluorometry techniques were utilized to record pore opening and voltage sensor movement of wild-type and mutant KCNQ1/I Ks channels. The clinical phenotypic penetrance of each LQT1 mutation was analyzed as a metric for assessing their clinical risk. The patient-specific–induced pluripotent stem-cell model was used to test mechanistic findings in physiological conditions. RESULTS: By systematically elucidating mechanisms of a series of LQT1 variants that lack cAMP sensitivity, we identified molecular determinants of I Ks channel regulation by phosphorylation. These key residues are distributed across the N-terminus of KCNQ1 extending to the central pore region of I Ks . We refer to this pattern as the I Ks channel PKA phosphorylation axis. Next, by examining LQT1 variants from clinical databases containing 10 579 LQT1 carriers, we found that the distribution of the most high-penetrance LQT1 variants extends across the I Ks channel PKA phosphorylation axis, demonstrating its clinical relevance. Furthermore, we found that a small molecule, ML277, which binds at the center of the phosphorylation axis, rescues the defective cAMP effects of multiple high-risk LQT1 variants. This finding was then tested in high-risk patient-specific induced pluripotent stem cell–derived cardiomyocytes, where ML277 remarkably alleviates the beating abnormalities. CONCLUSIONS: Our findings not only elucidate the molecular mechanism of PKA-dependent I Ks channel phosphorylation but also provide an effective antiarrhythmic strategy for patients with high-risk LQT1 variants.

01 Jun 2021·Journal of Periodontal ResearchQ2 · MEDICINE

Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras

Q2 · MEDICINE

Article

Author: Yang, Kai ; Wang, Ziming ; Meng, Liuyan ; Yang, Chengcan ; Peng, Yao ; Gao, Qian ; Chen, Dong ; Bian, Zhuan

AbstractBackground and ObjectiveActivated potassium channels were found to be strongly correlated with gingival overgrowth (GO) phenotype as we reviewed syndromic hereditary gingival fibromatosis (HGF). Nevertheless, the functional roles of potassium channels in gingival fibrosis or gingival overgrowth remained uncovered. The aim of the present study was to explore the pathogenic role of aberrantly activated potassium channel in Hereditary Gingival Fibromatosis (HGF).MethodsGingival tissues were collected from 9 HGF patients and 15 normal controls. Expression of KCNQ1 was detected by immunohistochemistry. Gingival fibroblasts were isolated, and outward K+ currents were detected by whole‐cell patch‐clamp analysis, transmembrane potential was determined by flow cytometry. Normal human gingival fibroblasts (NHGFs) were transfected with KCNQ1 adenovirus or treated with KCNQ1 selective agonist ML277 and antagonist chromanol 293B. Accumulation of Extracellular Matrix (ECM) was measured by Western blotting and Sircol Soluble Collagen Assay. Content of secreted TGF‐β1 was measured by ELISA. Active RAS pull‐down assay and cell immunofluorescence were utilized to verify RAS activation.ResultsKCNQ1 was upregulated in gingival tissues derived from HGF patients and HGF gingival fibroblasts presented increased outward K+ currents than NHGFs. Overexpression of KCNQ1, or KCNQ1 agonist ML277, promoted fibrotic responses of NHGFs. TGF‐β1 and KCNQ1 channels formed a positive feed‐back loop. ML277 generated lateral clustering and activation of Ras on plasma membrane, followed by augmented MAPK/AP‐1 signaling pathway output. JNK or ERK1/2 inhibitors suppressed ML277‐induced AP‐1 and ECM upregulation.ConclusionActivation of KCNQ1 potassium channel promoted fibrogenic responses in NHGFs via Ras/MAPK/AP‐1 signaling.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Preclinical	US	Vanderbilt University Medical Center	02 Aug 2012

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