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Regulation of Ion Channels by Membrane Lipids

Avia Rosenhouse‐Dantsker, Dolly Mehta, Irena Levitan

10.1002/cphy.c110001

Source: Volume 2, Issue 1, January 2012

Published online: January 2012

Full Article on Wiley Online Library



Abstract

The major membrane lipid regulators of ion channel function include cholesterol, one of the main lipid components of the plasma membranes, phosphoinositides, a group of regulatory phospholipids that constitute a minor component of the membrane lipids but are known to play key roles in regulation of multiple proteins and sphingolipids, particularly sphingosine‐1‐phosphate, a signaling biolipid that is generated from ceramide and is known to regulate multiple cellular functions. Furthermore, specific effects of all the lipid modulators are highly heterogeneous varying significantly between different types of ion channels, as well as between different cell types. In terms of the mechanisms, three general mechanisms have been shown to underlie lipid regulation of ion channels: specific lipid‐protein interactions, changes in the physical properties of the membrane, and facilitating the association of the channel proteins with other regulatory proteins within multiproteins signaling complexes termed membrane rafts. In this article, we present comprehensive analysis of the roles of several lipid modulators, including cholesterol, bile acids, phosphoinositides, and sphingolipids on ion channel function. © 2012 American Physiological Society. Compr Physiol 2:31‐68, 2012.

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Figure 1. Figure 1.

Structure of cholesterol molecule.
Figure 2. Figure 2.

Cholesterol sensitivity belt of Kir2.1 channels. Side view of a model of Kir2.1 that includes all four subunits. (A) Shown in the model are the residues whose mutation affects cholesterol sensitivity: D51 and H53 (cyan), E191 and V194 (blue), N216 and K219 (pink), L222 (red), and C311 (green). (B) Top view of the model of Kir2.1 from the membrane showing the cholesterol sensitivity belt formed by the residues whose mutation affects the cholesterol sensitivity of the channel. Adapted, with permission, from 298.
Figure 3. Figure 3.

Hydrophobic coupling between a bilayer‐embedded protein and its host lipid bilayer. (A) A protein conformational change causes a local bilayer deformation. (B) Formation of a gA channel involves local bilayer thinning. Adapted, with permission, from 202.
Figure 4. Figure 4.

Schematic diagram depicting the interaction of TRPC1 with caveolin‐1 (Cav‐1) in the lipid raft. TRPC1 interacts with the caveolin‐1 scaffolding domain within lipid rafts through its C‐terminus. This interaction is required for TRPC1‐mediated Ca2+ entry. Various lipids shown in the raft represent cholesterol, sphingolipids, and the side chains of the phospholipids highly enriched in saturated fatty acids.
Figure 5. Figure 5.

Structure of primary bile acids.
Figure 6. Figure 6.

Structure of PIP2.
Figure 7. Figure 7.

Types of residues involved in phosphoinositide‐binding sites. A histogram based on 25 complexed structures of phospoinositides bound to different proteins, as listed in Rosenhouse‐Dantsker and Logothetis 297. While the majority of the residues involved in interactions with phosphoinositides are positively charged, almost 40% of the residues that form the phosphoinositide binding site are not.
Figure 8. Figure 8.

Binding site of I(1,4,5)P3 to inositol trisphoshate (IP3) receptor. (A) Electrostatic potential of the binding site of I(1,4,5)P3 in IP3 receptor (PDB accession no. 1n4k), mapped on its molecular surface with a scale from red (negatively charged residues) to blue (positively charged residues). The core domain of the IP3 receptor is shown in ribbon presentation. (B) Detailed presentation of the binding site of I(1,4,5)P3 showing its extensive interactions with residues in the core domain of the IP3 receptor and water molecules. (C) Interactions between the core domain of IP3 receptor and I(1,4,5)P3 shown in a presentation that includes the core domain of the receptor. (D) Enlargement of the binding site of I(1,4,5)P3 depicted in C, showing the specific IP3 receptor residues that interact with the phosphoinositide.
Figure 9. Figure 9.

Structure of ceramide.
Figure 10. Figure 10.

Structure of sphingosine‐1‐phosphate (S1P).
Figure 11. Figure 11.

Model showing sphingosine‐1‐phosphate (S1P)‐induced activation of ion channels. Sphingosine kinase phosphorylates sphingosine (SPH) to generate S1P. S1P ligates with its receptor S1P1R which induces Gi activity leading to formation of inositol trisphoshate (IP3). IP3 induces Ca2+ release from endoplasmic reticulum (ER) followed by activation of Ca2+ entry through store‐operated calcium channel (SOC) (TRPC1/4). Sphingosine leads to activation of TRPM channel perhaps by inducing reactive oxidant species (ROS) generation. S1P also leads to activation of voltage‐gated Ca2+ channels as well as inward rectifying K+ channels (Kir) and large‐conductance potassium channels (BK) either directly or through S1P1 receptor pathway.
Figure 12. Figure 12.

Summary of the mechanisms for cholesterol regulation of ion channels and receptors.


Figure 1.

Structure of cholesterol molecule.



Figure 2.

Cholesterol sensitivity belt of Kir2.1 channels. Side view of a model of Kir2.1 that includes all four subunits. (A) Shown in the model are the residues whose mutation affects cholesterol sensitivity: D51 and H53 (cyan), E191 and V194 (blue), N216 and K219 (pink), L222 (red), and C311 (green). (B) Top view of the model of Kir2.1 from the membrane showing the cholesterol sensitivity belt formed by the residues whose mutation affects the cholesterol sensitivity of the channel. Adapted, with permission, from 298.



Figure 3.

Hydrophobic coupling between a bilayer‐embedded protein and its host lipid bilayer. (A) A protein conformational change causes a local bilayer deformation. (B) Formation of a gA channel involves local bilayer thinning. Adapted, with permission, from 202.



Figure 4.

Schematic diagram depicting the interaction of TRPC1 with caveolin‐1 (Cav‐1) in the lipid raft. TRPC1 interacts with the caveolin‐1 scaffolding domain within lipid rafts through its C‐terminus. This interaction is required for TRPC1‐mediated Ca2+ entry. Various lipids shown in the raft represent cholesterol, sphingolipids, and the side chains of the phospholipids highly enriched in saturated fatty acids.



Figure 5.

Structure of primary bile acids.



Figure 6.

Structure of PIP2.



Figure 7.

Types of residues involved in phosphoinositide‐binding sites. A histogram based on 25 complexed structures of phospoinositides bound to different proteins, as listed in Rosenhouse‐Dantsker and Logothetis 297. While the majority of the residues involved in interactions with phosphoinositides are positively charged, almost 40% of the residues that form the phosphoinositide binding site are not.



Figure 8.

Binding site of I(1,4,5)P3 to inositol trisphoshate (IP3) receptor. (A) Electrostatic potential of the binding site of I(1,4,5)P3 in IP3 receptor (PDB accession no. 1n4k), mapped on its molecular surface with a scale from red (negatively charged residues) to blue (positively charged residues). The core domain of the IP3 receptor is shown in ribbon presentation. (B) Detailed presentation of the binding site of I(1,4,5)P3 showing its extensive interactions with residues in the core domain of the IP3 receptor and water molecules. (C) Interactions between the core domain of IP3 receptor and I(1,4,5)P3 shown in a presentation that includes the core domain of the receptor. (D) Enlargement of the binding site of I(1,4,5)P3 depicted in C, showing the specific IP3 receptor residues that interact with the phosphoinositide.



Figure 9.

Structure of ceramide.



Figure 10.

Structure of sphingosine‐1‐phosphate (S1P).



Figure 11.

Model showing sphingosine‐1‐phosphate (S1P)‐induced activation of ion channels. Sphingosine kinase phosphorylates sphingosine (SPH) to generate S1P. S1P ligates with its receptor S1P1R which induces Gi activity leading to formation of inositol trisphoshate (IP3). IP3 induces Ca2+ release from endoplasmic reticulum (ER) followed by activation of Ca2+ entry through store‐operated calcium channel (SOC) (TRPC1/4). Sphingosine leads to activation of TRPM channel perhaps by inducing reactive oxidant species (ROS) generation. S1P also leads to activation of voltage‐gated Ca2+ channels as well as inward rectifying K+ channels (Kir) and large‐conductance potassium channels (BK) either directly or through S1P1 receptor pathway.



Figure 12.

Summary of the mechanisms for cholesterol regulation of ion channels and receptors.

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Article Title: Regulation of Ion Channels by Membrane Lipids
 

How to Cite

Avia Rosenhouse‐Dantsker, Dolly Mehta, Irena Levitan. Regulation of Ion Channels by Membrane Lipids. Compr Physiol 2012, 2: 31-68. doi: 10.1002/cphy.c110001