The nuclear envelope is increasingly viewed from an electrophysiological perspective by researchers interested in signal transduction pathways that influence gene transcription and other processes in the nucleus. Here, we describe evidence for ion channels and transporters in the nuclear membranes and for possible ion gating by the nuclear pores. We argue that a systems-level understanding of cellular regulation is likely to require the assimilation of nuclear electrophysiology into molecular and biochemical signaling pathways.
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http://dx.doi.org/10.1093/mp/ssq013 | DOI Listing |
PLoS One
December 2024
Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, China.
Obesity is associated with abnormal repolarization manifested by QT interval prolongation, and oxidative stress is an important link between obesity and arrhythmias. However, the underlying electrophysiological and molecular mechanisms remain unclear. The aim of this study is to evaluate the role of obesity in potassium current in ventricular myocytes and the potential mechanism of NADPH oxidase 2 (Nox2).
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10065.
This study shows that five membrane proteins-three GPCRs, an ion channel, and an enzyme-form self-clusters under natural expression levels in a cardiac-derived cell line. The cluster size distributions imply that these proteins self-oligomerize reversibly through weak interactions. When the concentration of the proteins is increased through heterologous expression, the cluster size distributions approach a critical distribution at which point a phase transition occurs, yielding larger bulk phase clusters.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
National Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China.
TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10065.
We examine the role of higher-order transient structures (HOTS) in M2R regulation of GIRK channels. Electron microscopic membrane protein location maps show that both proteins form HOTS that exhibit a statistical bias to be near each other. Theoretical calculations and electrophysiological measurements suggest that channel activity is isolated near larger M2R HOTS.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Department of Neuroscience, Farber Institute for Neuroscience and Jefferson Synaptic Biology Center, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA 19107.
Use-dependent spike broadening (UDSB) results from inactivation of the voltage-gated K (Kv) channels that regulate the repolarization of the action potential. However, the specific signaling and molecular processes that modulate UDSB have remained elusive. Here, we applied an adeno-associated viral vector approach and dynamic clamping to conclusively demonstrate how multisite phosphorylation of the N-terminal inactivation domain (NTID) of the Kv3.
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