Domain zipping and unzipping modulates TRPM4's properties in human cardiac conduction disease.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Wenying XianPeter Lipp

Abstract

The transient receptor potential melastatin 4 (TRPM4) is a Ca2+ -activated nonselective cation channel linked to human cardiac diseases. The human mutation K914R within TRPM4's S4-S5 linker was identified in patients with atrioventricular block. During UV-flash-mediated Ca2+ transients, TRPM4K914R  generated a threefold augmented membrane current concomitant with 2 to 3-fold slowed down activation and deactivation kinetics resulting in excessive membrane currents during human cardiac action potentials. Mutagenesis of K914 paired with molecular modeling suggested the importance of the nanoscopic interface between the S4-S5 linker, the MHR4-, and TRP-domain as a major determinant for TRPM4's behavior. Rational mutagenesis of an interacting amino acid (R1062Q) in the TRP domain was able to offset K914R`s gain-of-function by zipping and unzipping of this nanoscopic interface. In conclusion, repulsion and attraction between the amino acids at positions 914 and 1062 alters the flexibility of the nanoscopic interface suggesting a zipping and unzipping mechanism that modulates TRPM4's functions. Pharmacological modulation of this intramolecular mechanism might represent a novel therapeutic strategy for the management of TRPM4-mediated ...Continue Reading

References

Jun 12, 2003·The Journal of Biological Chemistry·Bernd NiliusVeit Flockerzi
Dec 14, 2004·The Journal of Biological Chemistry·Bernd NiliusMichael X Zhu
Apr 27, 2005·Nature Neuroscience·Tibor RohácsDiomedes E Logothetis
Jul 9, 2005·Science·Stephen B LongRoderick Mackinnon
May 9, 2006·Pflügers Archiv : European journal of physiology·Bernd Nilius, Rudi Vennekens
Feb 13, 2007·Nature Chemical Biology·Thomas VoetsBernd Nilius
Oct 26, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Nuria García-SanzAntonio Ferrer-Montiel
Sep 4, 2009·The Journal of Clinical Investigation·Martin KruseOlaf Pongs
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jun 16, 2010·Neuron·Barbara KremeyerAndrés Ruiz-Linares
Jun 22, 2010·Circulation. Cardiovascular Genetics·Hui LiuPatrice Bouvagnet
Feb 11, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Pierluigi ValenteAntonio Ferrer-Montiel
Mar 13, 2012·American Journal of Human Genetics·Zhimiao LinYong Yang
Feb 26, 2014·The Journal of General Physiology·Lucia Gregorio-TeruelAntonio Ferrer-Montiel
Mar 5, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jinfeng TengChing Kung
Apr 10, 2015·Nature·Candice E PaulsenDavid Julius
Oct 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Jinfeng TengChing Kung
Apr 19, 2017·Cell Calcium·Laura HofmannVeit Flockerzi
Dec 7, 2017·Nature·Paige A WinklerWei Lü
Dec 9, 2017·Science·Henriette E AutzenYifan Cheng
Feb 22, 2018·Proceedings of the National Academy of Sciences of the United States of America·Jingjing DuanDavid E Clapham
Dec 12, 2018·The Journal of Investigative Dermatology·Huijun WangZhimiao Lin

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Citations

Jul 25, 2021·International Journal of Molecular Sciences·Natthaphat Siri-AngkulJudith K Gwathmey

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