Abstract
Cholesterol modulates inwardly rectifying potassium (Kir) channels. A two-way molecular cytosolic switch controls channel modulation by cholesterol and PI(4,5)P(2). Cholesterol and PI(4,5)P(2) induce a common gating pathway of Kir2.1 despite their opposite impact on channel function. These findings provide insights into structure-function relationship of ion channels and contribute to understanding of the mechanisms underlying their regulation by lipids. Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating membrane excitability. An emerging feature of several Kir channels is that they are regulated by cholesterol. However, the mechanism by which cholesterol affects channel function is unclear. Here we show that mutations of two distant Kir2.1 cytosolic residues, Leu-222 and Asn-251, form a two-way molecular switch that controls channel modulation by cholesterol and affects critical hydrogen bonding. Notably, these two residues are linked by a residue chain that continues from Asn-251 to connect adjacent subunits. Furthermore, our data indicate that the same switch also regulates the sensitivity of the channels to phosphatidylinositol 4,5-bisphosphate, a phosphoinositide that is required for activation of Kir channels. Thus, although cholesterol and phosphatidylinositol 4,5-bisphosphate do not interact with the same region of Kir2.1, these different modulators induce a common gating pathway of the channel.
Highlights
Cholesterol modulates inwardly rectifying potassium (Kir) channels
Effect of L222I on Kir2.1: a Computational Analysis—To obtain initial insights into the molecular basis underlying the role of the cholesterol sensitivity belt residues in channel modulation, we carried out extensive molecular dynamics simulations of both the WT Kir2.1 and the L222I mutant
When examining the directions of the changes in the distances, it was evident that whereas several molecular surfaces in the C terminus exhibited increased distances relative to position 222 the distance between a number of other molecular surfaces and position 222 decreased (Fig. 1B). With this extensive structural perturbation spanning the majority of the C-terminal residues, intersubunit interactions were affected by the L222I mutation, explicating our previous data demonstrating that the L222I mutant has a dominant-negative effect on the sensitivity of the WT channel to cholesterol [23]
Summary
Cholesterol modulates inwardly rectifying potassium (Kir) channels. Results: A two-way molecular cytosolic switch controls channel modulation by cholesterol and PI[4,5]P2. We show that mutations of two distant Kir2.1 cytosolic residues, Leu-222 and Asn-251, form a two-way molecular switch that controls channel modulation by cholesterol and affects critical hydrogen bonding. These two residues are linked by a residue chain that continues from Asn-251 to connect adjacent subunits. Cholesterol and phosphatidylinositol 4,5-bisphosphate do not interact with the same region of Kir2.1, these different modulators induce a common gating pathway of the channel. Silent channels are retained on the plasma membrane but cannot be detected by single channel
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
