Submitted on February 6, 2008
Revised on June 27, 2008
Accepted on July 3, 2008
REGULATION OF CELL SURFACE EXPRESSION OF FUNCTIONAL PACEMAKER CHANNELS BY A MOTIF IN THE B-HELIX OF THE CYCLIC NUCLEOTIDE-BINDING DOMAIN
Hamed Nazzari1, Damiano Angoli1, Sarah S Chow, Gina Whitaker1, Leisha Leclair1, Evan MacDonald1, Vincenzo Macri1, Kristin Zahynacz1, Valerie Walker, and Eric A. Accili1*
1 UBC
* To whom correspondence should be addressed. E-mail: eaaccili{at}interchange.ubc.ca.
Previous studies have suggested that a portion of the cyclic nucleotide-binding domain (CNBD) of the HCN2 "pacemaker" channel, comprised of the A and B helices and the interceding 
-barrel, confers 2 functions: inhibition of channel opening in response to hyperpolarization and promotion of cell surface expression. The sequence determinants required for each of these functions is 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.
