Synergistic activation of G protein-gated inwardly rectifying potassium channels by cholesterol and PI(4,5)P2

Anna Bukiya, Avia Rosenhouse-Dantsker

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

G-protein gated inwardly rectifying potassium (GIRK or Kir3) channels play a major role in the control of the heart rate, and require the membrane phospholipid phosphatidylinositol-bis-phosphate (PI(4,5)P2) for activation. Recently, we have shown that the activity of the native heterotetrameric Kir3.1/Kir3.4 channel that underlies atrial KACh currents was enhanced by cholesterol. Similarly, the activities of both the Kir3.4 homomer and its active pore mutant Kir3.4* (Kir3.4_S143T) were also enhanced by cholesterol. Here we employ planar lipid bilayers to investigate the crosstalk between PI(4,5)P2 and cholesterol, and demonstrate that these two lipids act synergistically to activate Kir3.4* currents. Further studies using the Xenopus oocytes heterologous expression system suggest that PI(4,5)P2 and cholesterol act via distinct binding sites. Whereas PI(4,5)P2 binds to the cytosolic domain of the channel, the putative binding region of cholesterol is located at the center of the transmembrane domain overlapping the central glycine hinge region of the channel. Together, our data suggest that changes in the levels of two key membrane lipids - cholesterol and PI(4,5)P2 - could act in concert to provide fine-tuning of Kir3 channel function.

Original languageEnglish (US)
Pages (from-to)1233-1241
Number of pages9
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1859
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Inwardly Rectifying Potassium Channel
GTP-Binding Proteins
Chemical activation
Cholesterol
Phosphatidylinositol Phosphates
Lipid bilayers
Lipid Bilayers
Hinges
Membrane Lipids
Crosstalk
Xenopus
Phosphatidylinositols
Glycine
Oocytes
Phospholipids
Potassium
Tuning
Heart Rate
Phosphates
Binding Sites

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

Synergistic activation of G protein-gated inwardly rectifying potassium channels by cholesterol and PI(4,5)P2. / Bukiya, Anna; Rosenhouse-Dantsker, Avia.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1859, No. 7, 01.07.2017, p. 1233-1241.

Research output: Contribution to journalArticle

@article{0c5a93223909406c96e1bf5bc0d5abeb,
title = "Synergistic activation of G protein-gated inwardly rectifying potassium channels by cholesterol and PI(4,5)P2",
abstract = "G-protein gated inwardly rectifying potassium (GIRK or Kir3) channels play a major role in the control of the heart rate, and require the membrane phospholipid phosphatidylinositol-bis-phosphate (PI(4,5)P2) for activation. Recently, we have shown that the activity of the native heterotetrameric Kir3.1/Kir3.4 channel that underlies atrial KACh currents was enhanced by cholesterol. Similarly, the activities of both the Kir3.4 homomer and its active pore mutant Kir3.4* (Kir3.4_S143T) were also enhanced by cholesterol. Here we employ planar lipid bilayers to investigate the crosstalk between PI(4,5)P2 and cholesterol, and demonstrate that these two lipids act synergistically to activate Kir3.4* currents. Further studies using the Xenopus oocytes heterologous expression system suggest that PI(4,5)P2 and cholesterol act via distinct binding sites. Whereas PI(4,5)P2 binds to the cytosolic domain of the channel, the putative binding region of cholesterol is located at the center of the transmembrane domain overlapping the central glycine hinge region of the channel. Together, our data suggest that changes in the levels of two key membrane lipids - cholesterol and PI(4,5)P2 - could act in concert to provide fine-tuning of Kir3 channel function.",
author = "Anna Bukiya and Avia Rosenhouse-Dantsker",
year = "2017",
month = "7",
day = "1",
doi = "10.1016/j.bbamem.2017.03.023",
language = "English (US)",
volume = "1859",
pages = "1233--1241",
journal = "Biochimica et Biophysica Acta - Biomembranes",
issn = "0005-2736",
publisher = "Elsevier",
number = "7",

}

TY - JOUR

T1 - Synergistic activation of G protein-gated inwardly rectifying potassium channels by cholesterol and PI(4,5)P2

AU - Bukiya, Anna

AU - Rosenhouse-Dantsker, Avia

PY - 2017/7/1

Y1 - 2017/7/1

N2 - G-protein gated inwardly rectifying potassium (GIRK or Kir3) channels play a major role in the control of the heart rate, and require the membrane phospholipid phosphatidylinositol-bis-phosphate (PI(4,5)P2) for activation. Recently, we have shown that the activity of the native heterotetrameric Kir3.1/Kir3.4 channel that underlies atrial KACh currents was enhanced by cholesterol. Similarly, the activities of both the Kir3.4 homomer and its active pore mutant Kir3.4* (Kir3.4_S143T) were also enhanced by cholesterol. Here we employ planar lipid bilayers to investigate the crosstalk between PI(4,5)P2 and cholesterol, and demonstrate that these two lipids act synergistically to activate Kir3.4* currents. Further studies using the Xenopus oocytes heterologous expression system suggest that PI(4,5)P2 and cholesterol act via distinct binding sites. Whereas PI(4,5)P2 binds to the cytosolic domain of the channel, the putative binding region of cholesterol is located at the center of the transmembrane domain overlapping the central glycine hinge region of the channel. Together, our data suggest that changes in the levels of two key membrane lipids - cholesterol and PI(4,5)P2 - could act in concert to provide fine-tuning of Kir3 channel function.

AB - G-protein gated inwardly rectifying potassium (GIRK or Kir3) channels play a major role in the control of the heart rate, and require the membrane phospholipid phosphatidylinositol-bis-phosphate (PI(4,5)P2) for activation. Recently, we have shown that the activity of the native heterotetrameric Kir3.1/Kir3.4 channel that underlies atrial KACh currents was enhanced by cholesterol. Similarly, the activities of both the Kir3.4 homomer and its active pore mutant Kir3.4* (Kir3.4_S143T) were also enhanced by cholesterol. Here we employ planar lipid bilayers to investigate the crosstalk between PI(4,5)P2 and cholesterol, and demonstrate that these two lipids act synergistically to activate Kir3.4* currents. Further studies using the Xenopus oocytes heterologous expression system suggest that PI(4,5)P2 and cholesterol act via distinct binding sites. Whereas PI(4,5)P2 binds to the cytosolic domain of the channel, the putative binding region of cholesterol is located at the center of the transmembrane domain overlapping the central glycine hinge region of the channel. Together, our data suggest that changes in the levels of two key membrane lipids - cholesterol and PI(4,5)P2 - could act in concert to provide fine-tuning of Kir3 channel function.

UR - http://www.scopus.com/inward/record.url?scp=85017577947&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017577947&partnerID=8YFLogxK

U2 - 10.1016/j.bbamem.2017.03.023

DO - 10.1016/j.bbamem.2017.03.023

M3 - Article

VL - 1859

SP - 1233

EP - 1241

JO - Biochimica et Biophysica Acta - Biomembranes

JF - Biochimica et Biophysica Acta - Biomembranes

SN - 0005-2736

IS - 7

ER -