Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol Export

@article{citeulike:4510944, abstract = {10.1073/pnas.0809847106 A variety of ion channels are regulated by cholesterol, a major lipid component of the plasma membrane whose excess is associated with multiple pathological conditions. However, the mechanism underlying cholesterol sensitivity of ion channels is unknown. We have recently shown that an increase in membrane cholesterol suppresses inwardly rectifying K (Kir2) channels that are responsible for maintaining membrane potential in a variety of cell types. Here we show that cholesterol sensitivity of Kir2 channels depends on a specific region of the C terminus of the cytosolic domain of the channel, the CD loop. Within this loop, the L222I mutation in Kir2.1 abrogates the sensitivity of the channel to cholesterol whereas a reverse mutation in the corresponding position in Kir2.3, I214L, has the opposite effect, increasing cholesterol sensitivity. Furthermore, the L222I mutation has a dominant negative effect on cholesterol sensitivity of Kir2.1 WT. Mutations of 2 additional residues in the CD loop in Kir2.1, N216D and K219Q, partially affect the sensitivity of the channel to cholesterol. Yet, whereas these mutations have been shown to affect activation of the channel by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(,)P], other mutations outside the CD loop that have been previously shown to affect activation of the channel by PI(,)P had no effect on cholesterol sensitivity. Mutations of the lipid-facing residues of the outer transmembrane helix also had no effect. These findings provide insights into the structural determinants of the sensitivity of Kir2 channels to cholesterol, and introduce the critical role of the cytosolic domain in cholesterol dependent channel regulation.}, author = {Epshtein, Yulia and Chopra, Arun P. and Rosenhouse-Dantsker, Avia and Kowalsky, Gregory B. and Logothetis, Diomedes E. and Levitan, Irena}, citeulike-article-id = {4510944}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0809847106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/19/8055.short.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/19/8055.short.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19416905}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19416905}, day = {12}, doi = {10.1073/pnas.0809847106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {cholesterol, kir21, kir23, pip2, pip2-binding}, month = {May}, number = {19}, pages = {8055--8060}, posted-at = {2009-06-24 20:26:43}, priority = {2}, title = {Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol}, url = {http://dx.doi.org/10.1073/pnas.0809847106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:4510944 L3 - citeulike-article-id:4510944 N2 - 10.1073/pnas.0809847106 A variety of ion channels are regulated by cholesterol, a major lipid component of the plasma membrane whose excess is associated with multiple pathological conditions. However, the mechanism underlying cholesterol sensitivity of ion channels is unknown. We have recently shown that an increase in membrane cholesterol suppresses inwardly rectifying K (Kir2) channels that are responsible for maintaining membrane potential in a variety of cell types. Here we show that cholesterol sensitivity of Kir2 channels depends on a specific region of the C terminus of the cytosolic domain of the channel, the CD loop. Within this loop, the L222I mutation in Kir2.1 abrogates the sensitivity of the channel to cholesterol whereas a reverse mutation in the corresponding position in Kir2.3, I214L, has the opposite effect, increasing cholesterol sensitivity. Furthermore, the L222I mutation has a dominant negative effect on cholesterol sensitivity of Kir2.1 WT. Mutations of 2 additional residues in the CD loop in Kir2.1, N216D and K219Q, partially affect the sensitivity of the channel to cholesterol. Yet, whereas these mutations have been shown to affect activation of the channel by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(,)P], other mutations outside the CD loop that have been previously shown to affect activation of the channel by PI(,)P had no effect on cholesterol sensitivity. Mutations of the lipid-facing residues of the outer transmembrane helix also had no effect. These findings provide insights into the structural determinants of the sensitivity of Kir2 channels to cholesterol, and introduce the critical role of the cytosolic domain in cholesterol dependent channel regulation. IS - 19 JF - Proceedings of the National Academy of Sciences EP - 8060 TI - Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol VL - 106 SP - 8055 KW - cholesterol KW - kir21 KW - kir23 KW - pip2 KW - pip2-binding AU - Epshtein, Yulia AU - Chopra, Arun AU - Rosenhouse-Dantsker, Avia AU - Kowalsky, Gregory AU - Logothetis, Diomedes AU - Levitan, Irena PY - 2009/05/12/ UR - http://dx.doi.org/10.1073/pnas.0809847106 ER -