Key result
A four-amino acid motif (EEYP) in the B-helix of the HCN2 channel strongly promotes channel export from the endoplasmic reticulum and cell surface expression.
The study identifies a specific EEYP motif in the HCN2 pacemaker channel that is critical for its trafficking and cell surface expression, providing mechanistic insights into channel regulation.
Extends mechanistic insights into HCN channel expression; leaves open whether findings translate to arrhythmia therapies.
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.
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Nazzari et al. (2008) studied this question. EEYP motif in the B-helix of the HCN2 channel was evaluated on Channel export from the endoplasmic reticulum and cell surface expression. A four-amino acid motif (EEYP) in the B-helix of the HCN2 channel strongly promotes channel export from the endoplasmic reticulum and cell surface expression.
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