Review
Biochemistry & Molecular Biology
Lijuan Liang, Tatsuo Shimosawa
Summary: Chronic kidney disease (CKD) is a common and increasing clinical disease that affects 10 to 15% of the world's population. Hypertension is the most common and modifiable risk factor for adverse cardiovascular outcomes in CKD patients. The control rate of hypertension is low in both developed and developing countries, and CKD is not only a common cause of uncontrolled hypertension but also a risk factor for cardiovascular disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Cell Biology
Andree-Anne Marcoux, Laurence E. Tremblay, Samira Slimani, Marie-Jeanne Fiola, Fabrice Mac-Way, Alexandre P. Garneau, Paul Isenring
Summary: NKCC2 is an integral membrane protein that mediates the cotranslocation of Na+, K+, and Cl(-) ions in the TALH, allowing for the reclamation of a large fraction of filtered Na+, Cl-, Ca2+, Mg-2(+), and HCO(3)(-). Malfunction of NKCC2 can lead to various inherited disorders, illustrating its physiological importance.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Nur Farah Meor Azlan, Maarten P. Koeners, Jinwei Zhang
Summary: Hypertension, the leading cause of cardiovascular disease mortality worldwide, has been linked to alterations in the NCC and its regulatory mechanisms. Recent research has revealed significant progress in understanding the control of NCC, potentially identifying novel therapeutic targets for hypertension.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Peripheral Vascular Disease
Chuanming Xu, Yanting Chen, Fei Wang, Shiying Xie, Tianxin Yang
Summary: This study reveals a novel mechanism by which PRR and sPRR negatively regulate NCC activity through S1P, impacting renal excretion of salt and potassium and thus modulating blood pressure and potassium balance.
Article
Neurosciences
Abhishek Pethe, Mira Hamze, Marina Giannaki, Bernd Heimrich, Igor Medina, Anna-Maria Hartmann, Eleni Roussa
Summary: This study investigates the effects of KCC2/NBCe1 interaction on the phosphorylation pattern and function of KCC2. The results show that KCC2 and NBCe1 interact in the mouse brain and this interaction may have pathophysiological relevance.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2023)
Article
Physiology
Xin-Peng Duan, Peng Wu, Dan-Dan Zhang, Zhong-Xiuzi Gao, Yu Xiao, Evan C. Ray, Wen-Hui Wang, Dao-Hong Lin
Summary: Kir5.1 plays a significant role in mediating the effect of high sodium intake on basolateral K+ channels in the distal convoluted tubule and Na+-Cl- cotransporter activity/expression, and is involved in maintaining renal ability of K+ excretion during high sodium intake.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2021)
Article
Multidisciplinary Sciences
Minrui Fan, Jianxiu Zhang, Chien-Ling Lee, Jinru Zhang, Liang Feng
Summary: The sodium-chloride cotransporter (NCC) is crucial for kidney function and blood pressure regulation. This study used cryo-electron microscopy to determine the structure of human NCC and its interaction with a commonly prescribed thiazide diuretic. The findings provide important insights into the NCC's transport mechanism, as well as its regulation and interaction with thiazide diuretics, which are widely used for treating hypertension.
Article
Biochemistry & Molecular Biology
Hyun Ju Yoon, Gi-Cheon Kim, Sejin Oh, Hakhyun Kim, Yong Keon Kim, Yunji Lee, Min Seo Kim, Gino Kwon, Yeon-Su Ok, Ho-Keun Kwon, Hyun Seok Kim
Summary: Inhibiting the activity of the protein WNK3 can boost anti-tumor immunity by suppressing the production of another protein, PD-L1, that promotes the programmed cell death of immune system T cells. This research identified WNK3 inhibition as a potential new approach to treating cancer by affecting both immune system cells and cancer cells.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2022)
Article
Genetics & Heredity
Lorenzo Lones, Aaron Di Antonio
Summary: The research found that enhancing glial cells' ability to regulate lithium ions can suppress seizures. The study also found that the Wnk kinase regulates the buffering of lithium ions in glial cells through the transcription factor Fray, and overexpression of the Fray gene can effectively suppress seizure behavior in multiple epilepsy models. Finally, the study identified cortex glia as a key cell type in the susceptibility to seizures.
Review
Chemistry, Multidisciplinary
Erin McMoneagle, Jin Zhou, Shiyao Zhang, Weixue Huang, Sunday Solomon Josiah, Ke Ding, Yun Wang, Jinwei Zhang
Summary: Epilepsy is a neurological disorder characterized by seizures, and impaired function of the KCC2 protein has been found to contribute to its pathogenesis. Enhancing KCC2 activation and regulating its phosphorylation and transcription have shown promising results in attenuating seizure severity. Recent advances in understanding the regulatory mechanisms of KCC2 have led to the discovery of novel small molecules that modulate its activity, making it a potential therapeutic target for treating epilepsy.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Neurosciences
Jesper Edvardsson Rasmussen, Patrik Lundstrom, Per Olof Eriksson, Helge Rask-Andersen, Wei Liu, Goran Laurell
Summary: This study aimed to understand the acute effects of furosemide in the inner ear, including protein localization. The results showed rapid changes in NKCC1 induced by furosemide, and an increase in staining intensity of Fetuin-A and PEDF, possibly as an otoprotective response.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Hanxing Wan, Xiong Ying Chen, Fenglian Zhang, Jun Chen, Fenglan Chu, Zachary M. Sellers, Feng Xu, Hui Dong
Summary: In mouse models of ulcerative colitis, capsaicin exerts its anti-colitic action by inhibiting intestinal Cl- secretion and promoting Na+ absorption via blocking TRPV4 channels.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Mohammad Shahidullah, Joaquin Lopez Rosales, Nicholas Delamere
Summary: This study aimed to examine the function of piezo1 channel in the lens. The results showed that piezo1 activation stimulated Na,K-ATPase activity but did not affect NKCC activity. These findings provide insights into the functional role of piezo1 in lens physiology and warrant further investigation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Adya Saran Sinha, Tianying Wang, Miho Watanabe, Yasushi Hosoi, Eisei Sohara, Tenpei Akita, Shinichi Uchida, Atsuo Fukuda
Summary: The role of WNK3 in regulating intracellular Cl- concentration and excitability of neurons is still unclear. In this study, WNK3 knockout mice were used to investigate the effects of WNK3 on Cl- concentration and excitability of pyramidal neurons in the prefrontal cortex. The results showed that WNK3 knockout led to an increase in Cl- concentration and a decrease in excitability of neurons. Further experiments revealed that WNK3 is closely linked with the KCC2 channel in the regulation of resting K+ conductance.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2022)
Article
Urology & Nephrology
Soren B. Poulsen, Lei Cheng, David Penton, Marleen L. A. Kortenoeven, Vladimir V. Matchkov, Johannes Loffing, Robert Little, Sathish K. Murali, Robert A. Fenton
Summary: The beta 2-adrenergic receptor agonist salbutamol can increase NCC activity, affecting sodium and potassium homeostasis and potentially posing a risk factor for hypertension.
KIDNEY INTERNATIONAL
(2021)
Review
Cell Biology
Matthew Taylor, Dario R. Alessi
CURRENT OPINION IN CELL BIOLOGY
(2020)
Article
Multidisciplinary Sciences
Ying Fan, Francesca Tonelli, Shalini Padmanabhan, Marco A. S. Baptista, Lindsey Riley, Danielle Smith, Connie Marras, Andrew Howden, Dario R. Alessi, Esther Sammler
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2020)
Article
Biochemical Research Methods
Oezge Karayel, Francesca Tonelli, Sebastian Virreira Winter, Phillip E. Geyer, Ying Fan, Esther M. Sammler, Dario R. Alessi, Martin Steger, Matthias Mann
MOLECULAR & CELLULAR PROTEOMICS
(2020)
Article
Multidisciplinary Sciences
David E. Gordon, Joseph Hiatt, Mehdi Bouhaddou, Veronica V. Rezelj, Svenja Ulferts, Hannes Braberg, Alexander S. Jureka, Kirsten Obernier, Jeffrey Z. Guo, Jyoti Batra, Robyn M. Kaake, Andrew R. Weckstein, Tristan W. Owens, Meghna Gupta, Sergei Pourmal, Erron W. Titus, Merve Cakir, Margaret Soucheray, Michael McGregor, Zeynep Cakir, Gwendolyn Jang, Matthew J. O'Meara, Tia A. Tummino, Ziyang Zhang, Helene Foussard, Ajda Rojc, Yuan Zhou, Dmitry Kuchenov, Ruth Huttenhain, Jiewei Xu, Manon Eckhardt, Danielle L. Swaney, Jacqueline M. Fabius, Manisha Ummadi, Beril Tutuncuoglu, Ujjwal Rathore, Maya Modak, Paige Haas, Kelsey M. Haas, Zun Zar Chi Naing, Ernst H. Pulido, Ying Shi, Inigo Barrio-Hernandez, Danish Memon, Eirini Petsalaki, Alistair Dunham, Miguel Correa Marrero, David Burke, Cassandra Koh, Thomas Vallet, Jesus A. Silvas, Caleigh M. Azumaya, Christian Billesbolle, Axel F. Brilot, Melody G. Campbell, Amy Diallo, Miles Sasha Dickinson, Devan Diwanji, Nadia Herrera, Nick Hoppe, Huong T. Kratochvil, Yanxin Liu, Gregory E. Merz, Michelle Moritz, Henry C. Nguyen, Carlos Nowotny, Cristina Puchades, Alexandrea N. Rizo, Ursula Schulze-Gahmen, Amber M. Smith, Ming Sun, Iris D. Young, Jianhua Zhao, Daniel Asarnow, Justin Biel, Alisa Bowen, Julian R. Braxton, Jen Chen, Cynthia M. Chio, Un Seng Chio, Ishan Deshpande, Loan Doan, Bryan Faust, Sebastian Flores, Mingliang Jin, Kate Kim, Victor L. Lam, Fei Li, Junrui Li, Yen-Li Li, Yang Li, Xi Liu, Megan Lo, Kyle E. Lopez, Arthur A. Melo, Frank R. Moss, Phuong Nguyen, Joana Paulino, Komal Ishwar Pawar, Jessica K. Peters, Thomas H. Pospiech, Maliheh Safari, Smriti Sangwan, Kaitlin Schaefer, Paul Thomas, Aye C. Thwin, Raphael Trenker, Eric Tse, Tsz Kin Martin Tsui, Feng Wang, Natalie Whitis, Zanlin Yu, Kaihua Zhang, Yang Zhang, Fengbo Zhou, Daniel Saltzberg, Anthony J. Hodder, Amber S. Shun-Shion, Daniel M. Williams, Kris M. White, Romel Rosales, Thomas Kehrer, Lisa Miorin, Elena Moreno, Arvind H. Patel, Suzannah Rihn, Mir M. Khalid, Albert Vallejo-Gracia, Parinaz Fozouni, Camille R. Simoneau, Theodore L. Roth, David Wu, Mohd Anisul Karim, Maya Ghoussaini, Ian Dunham, Francesco Berardi, Sebastian Weigang, Maxime Chazal, Jisoo Park, James Logue, Marisa McGrath, Stuart Weston, Robert Haupt, C. James Hastie, Matthew Elliott, Fiona Brown, Kerry A. Burness, Elaine Reid, Mark Dorward, Clare Johnson, Stuart G. Wilkinson, Anna Geyer, Daniel M. Giesel, Carla Baillie, Samantha Raggett, Hannah Leech, Rachel Toth, Nicola Goodman, Kathleen C. Keough, Abigail L. Lind, Reyna J. Klesh, Kafi R. Hemphill, Jared Carlson-Stevermer, Jennifer Oki, Kevin Holden, Travis Maures, Katherine S. Pollard, Andrej Sali, David A. Agard, Yifan Cheng, James S. Fraser, Adam Frost, Natalia Jura, Tanja Kortemme, Aashish Manglik, Daniel R. Southworth, Robert M. Stroud, Dario R. Alessi, Paul Davies, Matthew B. Frieman, Trey Ideker, Carmen Abate, Nolwenn Jouvenet, Georg Kochs, Brian Shoichet, Melanie Ott, Massimo Palmarini, Kevan M. Shokat, Adolfo Garcia-Sastre, Jeremy A. Rassen, Robert Grosse, Oren S. Rosenberg, Kliment A. Verba, Christopher F. Basler, Marco Vignuzzi, Andrew A. Peden, Pedro Beltrao, Nevan J. Krogan
Article
Biochemistry & Molecular Biology
Asad U. Malik, Athanasios Karapetsas, Raja S. Nirujogi, Sebastian Mathea, Deep Chatterjee, Prosenjit Pal, Pawel Lis, Matthew Taylor, Elena Purlyte, Robert Gourlay, Mark Dorward, Simone Weidlich, Rachel Toth, Nicole K. Polinski, Stefan Knapp, Francesca Tonelli, Dario R. Alessi
Summary: Autosomal dominant mutations in LRRK2 enhance kinase activity and cause Parkinson's disease. LRRK2 phosphorylates Rab GTPases including Rab8A and Rab10. This study found that LRRK1 can phosphorylate Rab7A at Ser72, and identified mutations that enhance this phosphorylation.
BIOCHEMICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Raja S. Nirujogi, Francesca Tonelli, Matthew Taylor, Pawel Lis, Alexander Zimprich, Esther Sammler, Dario R. Alessi
Summary: This study introduces a new mass spectrometry assay for quantifying phosphorylated Rab substrates in different cells and tissues, finding that the VPS35[D620N] mutation enhances phosphorylation levels of multiple Rab proteins. This assay provides valuable insights into the impact of Parkinson's pathogenic mutations and inhibitors on LRRK2 Rab signaling pathways, showing that Rab1 is a physiological substrate for LRRK2 and highlighting the benefits over traditional immunoblotting approaches.
BIOCHEMICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Alexia F. Kalogeropulou, Jordana B. Freemantle, Pawel Lis, Edmundo G. Vides, Nicole K. Polinski, Dario R. Alessi
BIOCHEMICAL JOURNAL
(2020)
Article
Biochemistry & Molecular Biology
Suzannah J. Rihn, Andres Merits, Siddharth Bakshi, Matthew L. Turnbull, Arthur Wickenhagen, Akira J. T. Alexander, Carla Baillie, Benjamin Brennan, Fiona Brown, Kirstyn Brunker, Steven R. Bryden, Kerry A. Burness, Stephen Carmichael, Sarah J. Cole, Vanessa M. Cowton, Paul Davies, Chris Davis, Giuditta De Lorenzo, Claire L. Donald, Mark Dorward, James I. Dunlop, Matthew Elliott, Mazigh Fares, Ana da Silva Filipe, Joseph R. Freitas, Wilhelm Furnon, Rommel J. Gestuveo, Anna Geyer, Daniel Giesel, Daniel M. Goldfarb, Nicola Goodman, Rory Gunson, C. James Hastie, Vanessa Herder, Joseph Hughes, Clare Johnson, Natasha Johnson, Alain Kohl, Karen Kerr, Hannah Leech, Laura Sandra Lello, Kathy Li, Gauthier Lieber, Xiang Liu, Rajendra Lingala, Colin Loney, Daniel Mair, Marion J. McElwee, Steven McFarlane, Jenna Nichols, Kyriaki Nomikou, Anne Orr, Richard J. Orton, Massimo Palmarini, Yasmin A. Parr, Rute Maria Pinto, Samantha Raggett, Elaine Reid, David L. Robertson, Jamie Royle, Natalia Cameron-Ruiz, James G. Shepherd, Katherine Smollett, Douglas G. Stewart, Meredith Stewart, Elena Sugrue, Agnieszka M. Szemiel, Aislynn Taggart, Emma C. Thomson, Lily Tong, Leah S. Torrie, Rachel Toth, Margus Varjak, Sainan Wang, Stuart G. Wilkinson, Paul G. Wyatt, Eva Zusinaite, Dario R. Alessi, Arvind H. Patel, Ali Zaid, Sam J. Wilson, Suresh Mahalingam
Summary: The report introduces a range of tools for SARS-CoV-2 research, including a single plasmid reverse genetics system, a panel of antibodies, clinical isolates, and permissive cell lines. These tools have the potential to advance COVID-19 vaccine design, drug testing, and discovery science.
Article
Clinical Neurology
Martyna M. Grochowska, Ana Carreras Mascaro, Valerie Boumeester, Domenico Natale, Guido J. Breedveld, Hanneke Geut, Wiggert A. van Cappellen, Agnita J. W. Boon, Anneke J. A. Kievit, Esther Sammler, Piero Parchi, Pietro Cortelli, Dario R. Alessi, Wilma D. J. van de Berg, Vincenzo Bonifati, Wim Mandemakers
Summary: Loss-of-function variants in the LRP10 gene are linked to Parkinson's disease, dementia, and other neurodegenerative disorders. LRP10 is highly expressed in astrocytes and interacts with SORL1, potentially playing a crucial role in vesicle trafficking pathways. The specific pattern of LRP10 incorporation into Lewy bodies suggests its involvement in neurodegenerative diseases.
ACTA NEUROPATHOLOGICA
(2021)
Article
Clinical Neurology
Ying Fan, Raja S. Nirujogi, Alicia Garrido, Javier Ruiz-Martinez, Alberto Bergareche-Yarza, Elisabet Mondragon-Rezola, Ana Vinagre-Aragon, Ioana Croitoru, Ana Gorostidi Pagola, Laura Paternain Markinez, Roy Alcalay, Richard A. Hickman, Jonas During, Sara Gomes, Neringa Pratuseviciute, Shalini Padmanabhan, Francesc Valldeoriola, Leticia Perez Sisques, Cristina Malagelada, Teresa Ximelis, Laura Molina Porcel, Maria Jose Marti, Eduardo Tolosa, Dario R. Alessi, Esther M. Sammler
Summary: This study found a significant increase in pRab10(Thr73) phosphorylation in carriers of the LRRK2 R1441G mutation, whereas the effect of the LRRK2 G2019S mutation was not statistically significant. Analysis of pRab10(Thr73) phosphorylation in post-mortem brain samples revealed high variability mainly due to the adverse effects of the peri- and post-mortem period on protein phosphorylation stability.
ACTA NEUROPATHOLOGICA
(2021)
Article
Biochemistry & Molecular Biology
Anna Tasegian, Francois Singh, Ian G. Ganley, Alastair D. Reith, Dario R. Alessi
Summary: This study compares the properties of Type I and Type II kinase inhibitors binding to LRRK2 and finds that Type II inhibitors have stronger effects on LRRK2 activity but cannot induce dephosphorylation of specific sites, suggesting different mechanisms of action depending on the conformation of LRRK2.
BIOCHEMICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Dieter Waschbusch, Kerryn Berndsen, Pawel Lis, Axel Knebel, Yuko P. Y. Lam, Dario R. Alessi, Amir R. Khan
Summary: PPM1H acts against LRRK2 by dephosphorylating Rabs, with its flap domain identified as the specific interaction domain for Rabs. The crystal structure of PPM1H reveals a conserved phosphatase fold with a unique 110-residue flap domain, indicating an evolved mechanism for specific interaction with phosphorylated Rabs.
Article
Chemistry, Medicinal
Adam G. Bond, Conner Craigon, Kwok-Ho Chan, Andrea Testa, Athanasios Karapetsas, Rotimi Fasimoye, Thomas Macartney, J. Julian Blow, Dario R. Alessi, Alessio Ciulli
Summary: This study describes the design and development of a new protein degradation system utilizing a variant of the Brd4 bromodomain as a degradation tag. The system effectively degrades BromoTagged proteins in a fast, selective manner, showing favorable pharmacokinetic profile in mice. This system expands the arsenal of chemical genetic degradation tools for manipulating protein levels and exploring therapeutic potential in cells and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biology
Shahzad S. Khan, Yuriko Sobu, Herschel S. Dhekne, Francesca Tonelli, Kerryn Berndsen, Dario R. Alessi, Suzanne R. Pfeffer
Summary: Activating mutations of LRRK2 cause Parkinson's disease and result in cilia loss. The loss of cilia is associated with phosphorylation of Rab GTPases, defects in astrocytes, and dysregulation of the Hedgehog signaling pathway in the nigrostriatal pathway.
Article
Physiology
Mauricio Ostrosky-Frid, Maria Chavez-Canales, Jinwei Zhang, Olena Andrukhova, Eduardo R. Argaiz, Fernando Lerdo-de-Tejada, Adrian Murillo-de-Ozores, Andrea Sanchez-Navarro, Lorena Rojas-Vega, Norma A. Bobadilla, Norma Vazquez, Maria Castaneda-Bueno, Dario R. Alessi, Gerardo Gamba
Summary: The kidney-specific isoform of WNK1, KS-WNK1, is capable of stimulating the NaCl cotransporter by activating WNK4. Research shows that the activity of KS-WNK1 is influenced by specific amino acid residues.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2021)