Regulation of cell surface expression of functional pacemaker channels by a motif in the B-helix of the cyclic nucleotide-binding domain.
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.
Nazzari
Hamed
H
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Angoli
Damiano
D
Chow
Sarah S
SS
Whitaker
Gina
G
Leclair
Leisha
L
McDonald
Evan
E
Macri
Vincenzo
V
Zahynacz
Kristin
K
Walker
Valerie
V
Accili
Eric A
EA
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
C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels