Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss

The Journal of Clinical Investigation
Peijian HeC Chris Yun

Abstract

Diarrhea is one of the troublesome complications of diabetes, and the underlying causes of this problem are complex. Here, we investigated whether altered electrolyte transport contributes to diabetic diarrhea. We found that the expression of Na+/H+ exchanger NHE3 and several scaffold proteins, including NHE3 regulatory factors (NHERFs), inositol trisphosphate (IP₃) receptor-binding protein released with IP₃ (IRBIT), and ezrin, was decreased in the intestinal brush border membrane (BBM) of mice with streptozotocin-induced diabetes. Treatment of diabetic mice with insulin restored intestinal NHE3 activity and fluid absorption. Molecular analysis revealed that NHE3, NHERF1, IRBIT, and ezrin form macrocomplexes, which are perturbed under diabetic conditions, and insulin administration reconstituted these macrocomplexes and restored NHE3 expression in the BBM. Silencing of NHERF1 or IRBIT prevented NHE3 trafficking to the BBM and insulin-dependent NHE3 activation. IRBIT facilitated the interaction of NHE3 with NHERF1 via protein kinase D2-dependent phosphorylation. Insulin stimulated ezrin phosphorylation, which enhanced the interaction of ezrin with NHERF1, IRBIT, and NHE3. Additionally, oral administration of lysophosphatidic aci...Continue Reading

References

Feb 1, 1990·Archives of Internal Medicine·K I Ogbonnaya, R Arem
Feb 1, 1985·Annals of Internal Medicine·R N FedorakE B Chang
Apr 1, 1997·Proceedings of the National Academy of Sciences of the United States of America·C H YunMark Donowitz
Jul 14, 1998·Nature Genetics·P J SchultheisG E Shull
Oct 9, 1999·The Journal of Biological Chemistry·K KurashimaS Grinstein
Jun 9, 2000·Annual Review of Physiology·K E Barrett, S J Keely
Jun 8, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·U ChristenM G von Herrath
Jun 27, 2001·Free Radical Biology & Medicine·N E CameronM A Cotter
Aug 9, 2002·American Journal of Physiology. Renal Physiology·Jelena KlisicPatrice M Ambühl
Aug 10, 2002·Proceedings of the National Academy of Sciences of the United States of America·Shirish ShenolikarEdward J Weinman
Apr 3, 2003·The Journal of Clinical Investigation·Michael Field
Sep 5, 2003·American Journal of Physiology. Cell Physiology·Whaseon Lee-KwonMark Donowitz
Jun 16, 2004·Proceedings of the National Academy of Sciences of the United States of America·Huiren ZhaoJerrold R Turner
Feb 16, 2005·Annual Review of Physiology·Nicholas C ZachosMark Donowitz
Mar 25, 2005·Biochemical Society Transactions·R V FareseM L Standaert
May 13, 2005·American Journal of Physiology. Cell Physiology·Dongsheng WangC Chris Yun
Jul 9, 2005·The Journal of Pharmacology and Experimental Therapeutics·A FarhadiA Banan
Jun 14, 2006·Proceedings of the National Academy of Sciences of the United States of America·Kyoko ShirakabeKatsuhiko Mikoshiba
Oct 4, 2006·The Journal of Clinical Investigation·Daniel R ClayburghJerrold R Turner
Oct 5, 2006·American Journal of Physiology. Renal Physiology·Daniel G FusterOrson W Moe
Mar 10, 2007·Pflügers Archiv : European journal of physiology·Jutta HillesheimUrsula Seidler
Apr 27, 2007·Progress in Lipid Research·Laurens A van Meeteren, Wouter H Moolenaar
Aug 4, 2007·Kidney International. Supplement·H Noh, George L King
Sep 12, 2007·Journal of Proteome Research·Mark DonowitzXuhang Li
Oct 10, 2007·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Kyungmoo YeaSung Ho Ryu
May 16, 2008·American Journal of Physiology. Cell Physiology·Lixin ZhuJohn G Forte
Jun 23, 2009·Annals of the New York Academy of Sciences·Ursula SeidlerBrigitte Riederer
Sep 22, 2009·Current Gastroenterology Reports·Milena Gould, Joseph H Sellin
May 1, 2010·Circulation Research·Pedro Geraldes, George L King
Oct 14, 2010·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·B ChandrasekharanS Srinivasan

Citations

Apr 22, 2017·The Journal of Endocrinology·Alpana MathurPoonam Kakkar
Jun 10, 2016·American Journal of Physiology. Renal Physiology·Peijian HeC Chris Yun
May 25, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Kayte A JenkinC Chris Yun
Nov 14, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Luqing ZhaoPeijian He
Nov 28, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Songbai LinC Chris Yun
May 21, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Balasubramanian PalaniappanUma Sundaram
Mar 30, 2017·Proceedings of the National Academy of Sciences of the United States of America·Katsuhiro KawaaiKatsuhiko Mikoshiba
Dec 15, 2020·Pharmacology & Therapeutics·Jaana van GastelStuart Maudsley

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Hereditary Sensory Autonomic Neuropathy

Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.

Glut1 Deficiency

Glut1 deficiency, an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier, is characterized by mental and motor developmental delays and infantile seizures. Follow the latest research on Glut1 deficiency with this feed.

Regulation of Vocal-Motor Plasticity

Dopaminergic projections to the basal ganglia and nucleus accumbens shape the learning and plasticity of motivated behaviors across species including the regulation of vocal-motor plasticity and performance in songbirds. Discover the latest research on the regulation of vocal-motor plasticity here.

Neural Activity: Imaging

Imaging of neural activity in vivo has developed rapidly recently with the advancement of fluorescence microscopy, including new applications using miniaturized microscopes (miniscopes). This feed follows the progress in this growing field.

Nodding Syndrome

Nodding Syndrome is a neurological and epileptiform disorder characterized by psychomotor, mental, and growth retardation. Discover the latest research on Nodding Syndrome here.

LRRK2 & Microtubules

Mutations in the LRRK2 gene are risk-factors for developing Parkinson’s disease (PD). LRRK2 mutations in PD have been shown to enhance its association with microtubules. Here is the latest research.