Evolutionary emergence of N-glycosylation as a variable promoter of HCN channel surface expression

American Journal of Physiology. Cell Physiology
Andrew P HegleEric A Accili

Abstract

All four mammalian hyperpolarization-activated cyclic nucleotide-modulated (HCN) channel isoforms have been shown to undergo N-linked glycosylation in the brain. With the mouse HCN2 isoform as a prototype, HCN channels have further been suggested to require N-glycosylation for function, a provocative finding that would make them unique in the voltage-gated potassium channel superfamily. Here, we show that both the HCN1 and HCN2 isoforms are also predominantly N-glycosylated in the embryonic heart, where they are found in significant amounts and where HCN-mediated currents are known to regulate beating frequency. Surprisingly, we find that N-glycosylation is not required for HCN2 function, although its cell surface expression is highly dependent on the presence of N-glycans. Comparatively, disruption of N-glycosylation only modestly impacts cell surface expression of HCN1 and leaves permeation and gating functions almost unchanged. This difference between HCN1 and HCN2 is consistent with evolutionary trajectories that diverged in an isoform-specific manner after gene duplication from a common HCN ancestor that lacked N-glycosylation and was able to localize efficiently to the cell surface.

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Citations

Dec 4, 2012·Journal of Molecular Neuroscience : MN·Bermary Santos-VeraCarlos A Jiménez-Rivera
Dec 20, 2012·The Journal of Biological Chemistry·Alexandra MantIta O'Kelly
Jul 26, 2011·Current Opinion in Neurobiology·Yoav NoamTallie Z Baram
May 15, 2013·Circulation·François Roubille, Jean-Claude Tardif
Dec 27, 2018·Genes, Brain, and Behavior·Anne GüntherArnd Baumann
Jan 24, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wiebke WilkarsRoland A Bender
Nov 16, 2013·Molecular Biology Reports·Ana I CalejoPaula P Gonçalves
Apr 11, 2019·Molecular Biology of the Cell·Felix WiedmannConstanze Schmidt
Feb 23, 2019·Neurochemistry International·Bermary Santos-VeraCarlos A Jiménez-Rivera

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