title: Regulation of cell surface expression of functional pacemaker channels by a motif in the B-helix of the cyclic nucleotide-binding domain.
abstract: Previous studies have suggested that a portion of the cyclic nucleotide-binding domain (CNBD) of the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) "pacemaker" channel, composed of the A- and B-helices and the interceding beta-barrel, confers two functions: inhibition of channel opening in response to hyperpolarization and promotion of cell surface expression. The sequence determinants required for each of these functions are unknown. In addition, the mechanism underlying plasma membrane targeting by this subdomain has been limitedly explored. Here we identify a four-amino acid motif (EEYP) in the B-helix that strongly promotes channel export from the endoplasmic reticulum (ER) and cell surface expression but does not contribute to the inhibition of channel opening. This motif augments a step in the trafficking pathway and/or the efficiency of correct folding and assembly.
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Hamed
authors.initials: H
authors.lastname: Nazzari
authors.forename: Damiano
authors.initials: D
authors.lastname: Angoli
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Chow
authors.forename: Gina
authors.initials: G
authors.lastname: Whitaker
authors.forename: Leisha
authors.initials: L
authors.lastname: Leclair
authors.forename: Evan
authors.initials: E
authors.lastname: McDonald
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Macri
authors.forename: Kristin
authors.initials: K
authors.lastname: Zahynacz
authors.forename: Valerie
authors.initials: V
authors.lastname: Walker
authors.forename: Eric A
authors.initials: EA
authors.lastname: Accili
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001683:Biological Clocks; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000378:metabolism; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D015221:Potassium Channels; D017510:Protein Folding; D017433:Protein Structure, Secondary; D021381:Protein Transport; D014162:Transfection
chemical_list: C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels