title: A di-arginine ER retention signal regulates trafficking of HCN1 channels from the early secretory pathway to the plasma membrane.
abstract: Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels carry Ih, which contributes to neuronal excitability and signal transmission in the nervous system. Controlling the trafficking of HCN1 is an important aspect of its regulation, yet the details of this process are poorly understood. Here, we investigated how the C-terminus of HCN1 regulates trafficking by testing for its ability to redirect the localization of a non-targeted reporter in transgenic Xenopus laevis photoreceptors. We found that HCN1 contains an ER localization signal and through a series of deletion constructs, identified the responsible di-arginine ER retention signal. This signal is located in the intrinsically disordered region of the C-terminus of HCN1. To test the function of the ER retention signal in intact channels, we expressed wild type and mutant HCN1 in HEK293 cells and found this signal negatively regulates surface expression of HCN1. In summary, we report a new mode of regulating HCN1 trafficking: through the use of a di-arginine ER retention signal that monitors processing of the channel in the early secretory pathway.
authors.affiliation: Department of Biochemistry, Carver College of Medicine, University of Iowa, 51 Newton Road, Biochemistry, 4-712 BSB, Iowa City, IA, 52242, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Pan
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Laird
authors.forename: David M
authors.initials: DM
authors.lastname: Yamaguchi
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Baker
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D001120:Arginine / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010786:Photoreceptor Cells / Q000378:metabolism; D055571:Secretory Pathway; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D001120:Arginine