The surprising complexity of KATP channel biology and of genetic diseases

Zhao, Guiling; Kaplan, Aaron D.; Greiser, Maura; Lederer, W. Jonathan

doi:10.1172/jci135759

Cited by 8 publications

(8 citation statements)

References 32 publications

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“…Its structural heterogeneity leads to a variety of functions in different tissues. The SUR1/Kir6.1 or Kir6.2 and SUR2B/Kir6.2 K ATP channel subtypes are mainly expressed in the brain [ 44 ], whereas the Kir6.1 subunit is dominantly present in astrocytes, and the Kir6.2 subunit in neurons [ 45 , 46 ]. Given that ENSA has been proposed as a ligand of SUR1, we assessed whether SUR1 regulates NEP expression and/or activity in vivo.…”

Section: Resultsmentioning

confidence: 99%

Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway

et al. 2021

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Alzheimer’s disease (AD) is characterized by the deposition of amyloid β peptide (Aβ) in the brain. The neuropeptide somatostatin (SST) regulates Aβ catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here, we identified α-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (KATP) channel, as a negative regulator of NEP downstream of SST signaling. The expression of ENSA is significantly increased in AD mouse models and in patients with AD. In addition, NEP directly contributes to the degradation of ENSA, suggesting a substrate-dependent feedback loop regulating NEP activity. We also discovered the specific KATP channel subtype that modulates NEP activity, resulting in the Aβ levels altered in the brain. Pharmacological intervention targeting the particular KATP channel attenuated Aβ deposition, with impaired memory function rescued via the NEP activation in our AD mouse model. Our findings provide a mechanism explaining the molecular link between KATP channel and NEP activation, and give new insights into alternative strategies to prevent AD.

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Section: Resultsmentioning

confidence: 99%

Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway

et al. 2021

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“…CSMCs membrane depolarization generates action potentials and induces contraction. Therefore, it is possible to regulate conductance (such as non-selective cation channels) or hyperpolarized conductance (K + conductance) such as by K ATP channels, double-pore potassium channels, delayed rectification, and calcium-activated potassium by regulating the depolarization of gastrointestinal smooth muscle to regulate its electrophysiology and contraction [ 5 , 30 ]. In this study, we used a “Ca 2+ -free buffer” to exclude a role for Ca 2+ influx.…”

Section: Discussionmentioning

confidence: 99%

“…The increased expression and activity of K ATP channels contribute to decreased smooth muscle motility [ 4 ]. Previous studies suggested that K ATP channels (Kir6.1/SUR2B) expression in the vascular smooth muscle of T2DM rats was increased [ 5 ], therefore, we speculated that colonic smooth muscle contraction disorders might involve changes in K ATP expression in T2DM rats.…”

Section: Introductionmentioning

confidence: 96%

Effect of visfatin on KATP channel upregulation in colonic smooth muscle cells in diabetic colon dysmotility

Zhang

Wang

et al. 2022

Aging

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The mechanisms of diabetes-related gastrointestinal dysmotility remains unclear. This study aimed to investigate the effect and mechanisms of proinflammatory adipokine visfatin (VF) in the contractile dysfunction of diabetic rat colonic smooth muscle. Twenty Sprague-Dawley rats were randomly divided into control and type 2 diabetes mellitus groups. VF levels in the serum and colonic muscle tissues were tested, the time of the bead ejection and contractility of colonic smooth muscle strips were measured, and the expression of ATPsensitive potassium (K ATP ) channels in the colonic muscle tissues was analyzed. In vitro, we tested VF's effects on intracellular reactive oxygen species (ROS) levels, NF-κB's nuclear transcription, K ATP channel expression, intracellular Ca 2+ concentrations, and myosin light chain (MLC) phosphorylation in colonic smooth muscle cells (CSMCs). The effects of NAC (ROS inhibitor) and BAY 11-7082 (NF-κB inhibitor) on K ATP expression were also tested. Diabetic rats showed elevated VF levels in serum and colonic muscle tissues, a delayed distal colon ejection response time, weakened contractility of colonic smooth muscle strips, and increased K ATP channel expression in colonic muscle tissues. VF significantly inhibited the contractility of colonic smooth muscle strips from normal rats. In cultured CSMCs, VF caused ROS overload, increased NF-κB nuclear transcription activity and increased expression of Kir6.1, eventually reducing intracellular Ca 2+ levels and MLC phosphorylation. NAC and BAY 11-7082 inhibited the VF-induced Kir6.1 upregulation. In conclusion, VF may cause contractile dysfunction of CSMCs by upregulating the expression of the Kir6.1 subunit of K ATP channels via the ROS/NF-κB pathway and interfering with Ca 2+ signaling.

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“…K ATP channels are octameric protein complexes containing 4 pore-forming Kir6 subunits and 4 accessory sulfonylurea receptor (SUR) subunits. Two Kir6.x genes (KCNJ8 for Kir6.1, and KCNJ11 for Kir6.2) and two SUR genes (ABCC8 for SUR1 and ABCC9 for SUR2A and SUR2B) have been identified 7 . K ATP , including Kir6.1 and SUR2 proteins, are critical in regulating vascular tone, particularly in coronary arteries.…”

Section: Introductionmentioning

confidence: 99%

Primer Raynaud fenomeni olgularında ATP-bağımlı potasyum kanal proteinlerini kodlayan genlerde rastlanan varyasyonların belirlenmesi

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Yıldırım

VEZİR

et al. 2023

Cukurova Medical Journal

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Purpose: Primary Raynaud’s phenomenon (PRP) is a vascular disorder characterized by recurrent vasospastic response of the fingers and toes to cold or stress. ATP-sensitive potassium (KATP) channels are widely distributed in vasculatures, and play an important role in the vascular tone regulation. The major vascular isoform of KATP channels is composed of Kir6.1/SUR2 (KCNJ8/ABCC9). It would be important to determine whether variations of KATP genes related to PRP is thought to be associated with vasospasm. It is believed that the studies describing mechanisms involved in the pathogenesis of inherited vascular disorders offers the best opportunity for investigation of the early stages of pathogenicity and diagnosis of PRP and associated other diseases. In this study we aim to investigate possible association between genetic variations observed in KATP channel coding genes and vasospasm associated with PRP. Materials and Methods: In our study; the cases with PRP, the relation between the variation in the KCNJ8/ABCC9 genes (S422L/V734I or rs72554071/rs61688134) was examined. 50 subjects who were diagnosed with PRP (patient group) and 50 healthy subjects (control group) were included in the study. Variations were determined using the Tetra-Primer Amplification Refractory Mutation System-Polymerase Chain Reaction (T-ARMS PCR) method. Results: Of the individuals in the patient and control group included in the study, 21 were male and 29 were female. The mean age of the patients was 25.7±3.36 years, and the mean age of the control group was 25.9±3.44 years. No significant relationship was found between PRP disease and genotype and allele distribution of KCNJ8/ABCC9 genes. Conclusion: This study presented the first findings about KCNJ8/ABCC9 gene variations in the Turkish population and may lead to future studies. Studies involving a higher number of cases and more mutations will be able to show whether there is a relationship between KATP channels and PRP and contribute to the elucidation of PRP pathogenesis in terms of genetic factors.

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The surprising complexity of KATP channel biology and of genetic diseases

Cited by 8 publications

References 32 publications

Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway

Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway

Effect of visfatin on KATP channel upregulation in colonic smooth muscle cells in diabetic colon dysmotility

Primer Raynaud fenomeni olgularında ATP-bağımlı potasyum kanal proteinlerini kodlayan genlerde rastlanan varyasyonların belirlenmesi

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