Regulation of cell surface expression of functional pacemaker channels by a motif in the B-helix of the cyclic nucleotide-binding domain.

Hamed Nazzari, Damiano Angoli, Sarah S Chow, Gina Whitaker, Leisha Leclair, Evan McDonald, Vincenzo Macri, Kristin Zahynacz, Valerie Walker, Eric A Accili

Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

American journal of physiology. Cell physiology 2008 Sep

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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.

Citation

Hamed Nazzari, Damiano Angoli, Sarah S Chow, Gina Whitaker, Leisha Leclair, Evan McDonald, Vincenzo Macri, Kristin Zahynacz, Valerie Walker, Eric A Accili. Regulation of cell surface expression of functional pacemaker channels by a motif in the B-helix of the cyclic nucleotide-binding domain. American journal of physiology. Cell physiology. 2008 Sep;295(3):C642-52