期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 594, 期 7, 页码 1821-1840出版社
WILEY
DOI: 10.1113/JP271690
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资金
- Canadian Institutes of Health Research
- Leverhulme Trust [RPG-059]
- Medical Research Council [MR/M0004331]
- Fonds de Recherche en Sante du Quebec
- Banting and Best graduate fellowship from the CIHR
- Canada Research Chair
- Alfred Benzon Foundation
- UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim [EP/L000253/1]
- Office of Science and Technology through EPSRC's High End Computing Programme
- EPSRC [EP/L000253/1] Funding Source: UKRI
- MRC [MR/M000435/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/L000253/1] Funding Source: researchfish
- Medical Research Council [MR/M000435/1] Funding Source: researchfish
Channel block and permeation by cytoplasmic polyamines is a common feature of many cation-selective ion channels. Although the channel block mechanism has been studied extensively, polyamine permeation has been considered less significant as it occurs at extreme positive membrane potentials. Here, we show that kainate receptor (KAR) heteromerization and association with auxiliary proteins, Neto1 and Neto2, attenuate polyamine block by enhancing blocker permeation. Consequently, polyamine permeation and unblock occur at more negative and physiologically relevant membrane potentials. In GluK2/GluK5 heteromers, enhanced permeation is due to a single proline residue in GluK5 that alters the dynamics of the -helical region of the selectivity filter. The effect of auxiliary proteins is additive, and therefore the structural basis of polyamine permeation and unblock is through a different mechanism. As native receptors are thought to assemble as heteromers in complex with auxiliary proteins, our data identify an unappreciated impact of polyamine permeation in shaping the signalling properties of neuronal KARs and point to a structural mechanism that may be shared amongst other cation-selective ion channels.
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