Abstract
The slow inactivation of voltage-gated potassium (Kv) channels plays an important role in controlling cellular excitability. Recently, the two hydrogen bonds (H-bonds) formed by W434-D447 and T439-Y445 have been reported to control the slow inactivation in Shaker potassium channels. The four residues are highly conserved among Kv channels. Our objective was to find the roles of the two H-bonds in controlling the slow inactivation of mammalian Kv2.1, Kv2.2, and Kv1.2 channels by point mutation and patch-clamp recording studies. We found that mutations of the residues equivalent to W434 and T439 in Shaker did not change the slow inactivation of the Kv2.1, Kv2.2, and Kv1.2 channels. Surprisingly, breaking of the inter-subunit H-bond formed by W366 and Y376 (Kv2.1 numbering) by various mutations resulted in the complete loss of K+ conductance of the three Kv channels. In conclusion, we found differences in the H-bonds controlling the slow inactivation of the mammalian Kv channels and Shaker channels. Our data provided the first evidence, to our knowledge, that the inter-subunit H-bond formed by W366 and Y376 plays an important role in regulating the K+ conductance of mammalian Kv2.1, Kv2.2, and Kv1.2 channels.
Highlights
Mammalian voltage-gated potassium (Kv) channels, consisting of 12 subfamilies (Kv1-12), including 40 subtypes, play key roles in maintaining the membrane potential and mediating neuronal and muscular excitability and have been implicated in various neuronal and cardiovascular diseases [1,2,3]
The four residues, forming the two Hydrogen bonds (H-bonds) (W434-D447 and T439-Y445) in Shaker channels, are highly conserved among the Kv channels and may form H-bonds in mammalian Kv channels according to the structure of the Kv1.2/Kv2.1 chimeric channel (PDB: 2R9R)
We tested whether the H-bonds controlling the slow inactivation in Shaker channels play important roles in the rat Kv2.1, Kv2.2, and Kv1.2 channels in HEK293 cells
Summary
Mammalian voltage-gated potassium (Kv) channels, consisting of 12 subfamilies (Kv1-12), including 40 subtypes, play key roles in maintaining the membrane potential and mediating neuronal and muscular excitability and have been implicated in various neuronal and cardiovascular diseases [1,2,3]. Hydrogen bonds (H-bonds) between the selectivity filter and the adjacent pore helix are considered as major regulators of the slow inactivation. Pless et al recently demonstrated that an intra-subunit H-bond formed by W434-D447 and an intersubunit H-bond formed by T439-Y445 regulate the slow inactivation of Shaker channels [15]. Besides these four residues, T449 is shown to play important roles in regulating the slow inactivation of Shaker channels [16]. The four residues, forming the two H-bonds (W434-D447 and T439-Y445) in Shaker channels, are highly conserved among the Kv channels and may form H-bonds in mammalian Kv channels according to the structure of the Kv1.2/Kv2.1 chimeric channel (PDB: 2R9R)
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