Ion Channel Trafficking
Ion Channel Trafficking
Research Topics uitklapper, klik om te openen
A balanced expression of cardiac ion channels at the sarcolemma is of crucial importance for normal action potential formation and thus cardiac function. The cellular processes that transport channel proteins from the endoplasmic reticulum towards specified regions on the sarcolemmal membrane, and subsequently take them from the plasma membrane to the protein degradation machinery are commonly known as antegrade and retrograde transport, respectively. We recognize that aberrant channel trafficking stands at the basis of many congenital and acquired arrhythmias. At the department of Medical Physiology, we focus on trafficking of the repolarizing ion channels that underlie IKr and IK1. We are beginning to learn that ion channels traffic in channel-specific pathways using particular interacting proteins that target them to their destination membranes. We make use of a multidisciplinary approach that incorporates robust molecular and cell biology, state-of-the-art cellular imaging techniques and advanced electrophysiological readout methods and translates its findings to the clinic. We started initiatives to transit our cardiac ion channel trafficking research from ectopic cell expression systems, via isolated adult cardiomyocytes and tissue explants into in vivo approaches. This new knowledge will not only permit a more detailed understanding of pathophysiological mechanisms of cardiac arrhythmias but will also allow designing new therapeutic approaches and safer drugs.
Key Publications uitklapper, klik om te openen
Qile M, Ji Y, Golden TD, Houtman MJC, Romunde F, Fransen D, van Ham WB, IJzerman AP, January CT, Heitman LH, Stary-Weinzinger A, Delisle BP, van der Heyden MAG. LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1. Mol Pharmacol. 2020 Jun;97(6):355-364. doi: 10.1124/mol.119.118190. Epub 2020 Apr 2. PMID: 32241959.
Ji Y, Veldhuis MG, Zandvoort J, Romunde FL, Houtman MJC, Duran K, van Haaften G, Zangerl-Plessl EM, Takanari H, Stary-Weinzinger A, van der Heyden MAG. PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KIR2.1 channels, but increases channel protein expression. J Biomed Sci. 2017 Jul 15;24(1):44. doi: 10.1186/s12929-017-0352-x. PMID: 28711067; PMCID: PMC5513211.
Varkevisser R, Houtman MJ, Linder T, de Git KC, Beekman HD, Tidwell RR, Ijzerman AP, Stary-Weinzinger A, Vos MA, van der Heyden MA. Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue. Br J Pharmacol. 2013 Jul;169(6):1322-34. doi: 10.1111/bph.12208. PMID: 23586323; PMCID: PMC3831711.
de Git KC, de Boer TP, Vos MA, van der Heyden MA. Cardiac ion channel trafficking defects and drugs. Pharmacol Ther. 2013 Jul;139(1):24-31. doi: 10.1016/j.pharmthera.2013.03.008. Epub 2013 Apr 2. PMID: 23558293.
Varkevisser R, Houtman MJ, Waasdorp M, Man JC, Heukers R, Takanari H, Tieland RG, van Bergen En Henegouwen PM, Vos MA, van der Heyden MA. Inhibiting the clathrin-mediated endocytosis pathway rescues K(IR)2.1 downregulation by pentamidine. Pflugers Arch. 2013 Feb;465(2):247-59. doi: 10.1007/s00424-012-1189-5. Epub 2012 Nov 29. PMID: 23192368.
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Marcel van der Heyden