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HCN channels are thought to be structurally similar to K v  channels, but show much lower selectivity for K + . The ∼3.3 Å selectivity filter of K +  channels is formed by the pore-lining sequence XT(V/I)GYG, with X usually T, and is held stable by key residues in the P-loop. Differences in the P-loop sequence of HCN channels (eg. the pore-lining sequence L 478 C 479 IGYG) suggest these residues could account for differences in selectivity between these channel families. Despite being expressed, L478T/C479T HCN4 channels did not produce current. Since threonine in the second position is highly conserved in K +  channels, we also studied C479T channels. Based on permeability ratios (P X /P K ), C479T HCN4 channels (K + (1)>Rb + (0.85)>Cs + (0.59)>Li + (0.50)≥Na + (0.49)) were less selective than WT rabbit HCN4 (K + (1)>Rb + (0.48)>Cs + (0.31)≥Na + (0.29)>Li + (0.03)), indicating that the TIGYG sequence is insufficient to confer K +  selectivity to HCN channels. C479T HCN4 channels had an increased permeability to large organic cations than WT HCN4 channels, as well as increased unitary K +  conductance, and altered channel gating. Collectively, these results suggest that HCN4 channels have larger pores than K +  channels and replacement of the cysteine at position 479 with threonine further increases pore size. Furthermore, selected mutations in other regions linked previously to pore stability in K +  channels (ie. S475D, S475E and F471W/K472W) were also unable to confer K +  selectivity to C479T HCN4 channels. Our findings establish the presence of the TIGYG pore-lining sequence does not confer K +  selectivity to rabbit HCN4 channels, and suggests that differences in selectivity of HCN4 versus K +  channels originate from differences outside the P-loop region.

P-Loop Residues Critical for Selectivity in K+ Channels Fail to Confer Selectivity to Rabbit HCN4 Channels