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Review
, 1851 (5), 620-8

Lipid Agonism: The PIP2 Paradigm of Ligand-Gated Ion Channels

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Review

Lipid Agonism: The PIP2 Paradigm of Ligand-Gated Ion Channels

Scott B Hansen. Biochim Biophys Acta.

Abstract

The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid-ligand bind to a membrane protein in the plasma membrane, and what does it mean for a lipid to activate or regulate an ion channel? How does lipid binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular, ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.

Keywords: G-protein; Ion channel; Lipid gated; Lipid raft; PIP(2); Signaling lipid.

Conflict of interest statement

Conflict of interest.

The author declares no conflict of interest.

Figures

Fig. 1
Fig. 1
PIP2 lipid regulation of ion channels. A, The chemical structure of plasma membrane PIP2 is shown with an arachidonyl acyl chain (green) and inositol phosphates at the 4′ and 5′ position (red). B, a cartoon representation of a PIP2 lipid gated ion channel. PIP2 is shown bound to a lipid binding site in the transmembrane domain of an ion channel. C, List of ion channels with lipid gating properties. Kir2.2 and 3.2 are the most clearly “lipid-gated”. A second group appears to be dual regulated, or “PIP2 modulated”. PIP2 modulates channel gating, but gating also requires either voltage or a second ligand. A third group of channels behave similar to Kir but await definitive proof of lipid gating vs. PIP2 modulation (?). The list of channels is exemplary and not comprehensive.
Fig. 2
Fig. 2
Conserved PIP2 binding site in Kir2.2. PIP2 binds the transmembrane domain (TMD) of Kir and causes a conformational change that allosterically gates the channel. A, The PIP2 binding site is specific for inositol 5′ phosphate. B, A sequence alignment of all Kir family members reveals a highly structured PIP2 binding site comprised of basic residues. Amino acid residues that directly contact PIP2 are shown in bold type. Only two residues (brown type) at the conserved site lack a positive charge. Residues originating from the TMD and a linker (LNK) are shaded green and grey respectively. ^ indicates residues that strongly coordinate the lipid backbone phosphate, * indicates the residues that strongly (red) and weakly (grey) bind the PIP2 5′ phosphate. PIP2 atoms are colored yellow, carbon, orange phosphate; red oxygen. Amino acid side chains with carbons colored green are located on transmembrane outer helix 1 (TM1) or inner helix 2 (TM2). Lysines colored grey are located on the start of a linker helix (LNK) or “tether helix” connecting the transmembrane domain (TMD) and the cytoplasmic domain (CTD). Residue numbering is according to Kir2.2.
Fig. 3
Fig. 3
Mechanistic comparison of surface charge gating vs. direct lipid gating. A, Non-specific surface charge gates an ion channel through a charge sensor domain (blue). The vertical arrow indicates charge driven movement. B, A lipid-gated channel reversibly binds the signaling lipid PIP2 to allosterically gate the channel. A horizontal arrow indicates PIP2 dissociation from the channel.
Fig. 4
Fig. 4
Phosphoinositide (PI) partitioning in the plasma membrane. In the absence of a stimulus, arachidonyl-PIP2 (green) localizes in the disordered region of the plasma membrane and sometimes in concentrated lipid micro domains (dark green) apart from cholesterol-rich lipid-rafts (red). Inositol lipids are distributed according to their acyl chains; hence, saturated PIP2 enters lipid rafts where PI3 kinase generates PIP3. A saturated lysoPIP2 may also associates with raft like domains. Key signaling enzymes (see colored boxes) appear localized in lipid micro domains where they are optimally positioned to remodel the PIP acyl chains and head groups during signaling. Lipid degradation products are found in endocytic vesicles, which suggest a lipid-recycling event analogous to recycling of some soluble neurotransmitters. Grey diamond represents PI3 kinase.
Fig. 5
Fig. 5
PIP2 transient signaling. A, In the proposed model, PIP2 dissociates from Kir and diffuses laterally in the plasma membrane. G proteins activate lipid-hydrolyzing enzymes that deplete PIP2 from the plasma membrane or laterally redistribute PIP2 into distinct lipid micro domains (e.g. lipid rafts). Dynamic PIP2 signaling gives rise to a transient inactivation of Kir that contributes to an action potential. B, PIP2 degradation products are taken up by endocytosis and PIP2 resynthesis returns the cell to a resting state.

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