The beta-cell ATP-sensitive potassium (KATP) channel controls insulin secretion by linking glucose metabolism to membrane excitability. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes that encode the sulfonylurea receptor 1 or the inward rectifier Kir6.2 subunit of the channel, is a major cause of congenital hyperinsulinism. Here, we report identification of a novel KCNJ11 mutation associated with the disease that renders a missense mutation, F55L, in the Kir6.2 protein. Mutant channels reconstituted in COS cells exhibited a wild-type-like surface expression level and normal sensitivity to ATP, MgADP, and diazoxide. However, the intrinsic open probability of the mutant channel was greatly reduced, by approximately 10-fold. This low open probability defect could be reversed by application of phosphatidylinositol 4,5-bisphosphates or oleoyl-CoA to the cytoplasmic face of the channel, indicating that reduced channel response to membrane phospholipids and/or long chain acyl-CoAs underlies the low intrinsic open probability in the mutant. Our findings reveal a novel molecular mechanism for loss of KATP channel function and congenital hyperinsulinism and support the importance of phospholipids and/or long chain acyl-CoAs in setting the physiological activity of beta-cell KATP channels. The F55L mutation is located in the slide helix of Kir6.2. Several permanent neonatal diabetes-associated mutations found in the same structure have the opposite effect of increasing intrinsic channel open probability. Our results also highlight the critical role of the Kir6.2 slide helix in determining the intrinsic open probability of KATP channels.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1479853 | PMC |
http://dx.doi.org/10.1074/jbc.M511875200 | DOI Listing |
JAMA Netw Open
January 2025
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Importance: Disease characteristics of genetically mediated coronary artery disease (CAD) on coronary angiography and the association of genomic risk with outcomes after coronary angiography are not well understood.
Objective: To assess the angiographic characteristics and risk of post-coronary angiography outcomes of patients with genomic drivers of CAD: familial hypercholesterolemia (FH), high polygenic risk score (PRS), and clonal hematopoiesis of indeterminate potential (CHIP).
Design, Setting, And Participants: A retrospective cohort study of 3518 Mass General Brigham Biobank participants with genomic information who underwent coronary angiography was conducted between July 18, 2000, and August 1, 2023.
JAMA Netw Open
January 2025
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Importance: Secondary lymphedema is a common, harmful side effect of breast cancer treatment. Robust risk models that are externally validated are needed to facilitate clinical translation. A published risk model used 5 accessible clinical factors to predict the development of breast cancer-related lymphedema; this model included a patient's mammographic breast density as a novel predictive factor.
View Article and Find Full Text PDFJAMA Netw Open
January 2025
Department of Family Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
Importance: There is limited evidence regarding the association between age at menopause and incident type 2 diabetes (T2D).
Objective: To investigate whether age at menopause and premature menopause are associated with T2D incidence in postmenopausal Korean women.
Design, Setting, And Participants: This population-based cohort study was conducted among a nationally representative sample from the Korean National Health Insurance Service database of 1 125 378 postmenopausal women without T2D who enrolled in 2009.
Sci Rep
January 2025
College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
Parkinson's disease (PD), as the second most prevalent neurodegenerative disorder worldwide, impacts the quality of life for over 12 million patients. This study aims to enhance the accuracy of early diagnosis of PD through non-invasive methods, with the goal of enabling earlier intervention in the disease process. To this end, we constructed an open-field environment using flexible sensors under dark conditions, conducting experiments on a mouse model of Parkinson's disease alongside a normal control group.
View Article and Find Full Text PDFBMJ Open
January 2025
Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Objective: Adverse childhood experiences (ACE) have inconsistently been implicated as risk factors for immune-mediated inflammatory diseases (IMID). We evaluated whether the association of ACE with disease differs between IMID and other chronic diseases.
Design: Nested retrospective case-control study.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!