Lipid-gated ion channels

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Lipid-gated ion-channel Kir2.2
TREK PIP2.png
Tetrameric Kir2.2 (grey trace) bound to four PIP2 molecules (carbon:yellow; oxygen:red). Potassium ions (purple) are shown in the open conduction pathway. Grey rectangles indicate the membrane border.
Identifiers
SymbolKir2.2
OPM protein 3SPG

Lipid-gated ion channels are a class of ion channels whose conductance of ions through the membrane depends directly on lipids. Classically the lipids are membrane resident anionic signaling lipids that bind to the transmembrane domain on the inner leaflet of the plasma membrane with properties of a classic ligand. Other classes of lipid-gated channels include the mechanosensitive ion channels that respond to lipid tension, thickness, and hydrophobic mismatch. A lipid ligand differs from a lipid cofactor in that a ligand derives its function by dissociating from the channel while a cofactor typically derives its function by remaining bound. [1]

Contents

PIP2-gated channels

Phosphatidylinositol 4,5-bisphosphate (PIP2) was the first and remains the best studied lipid to gate ion channels. PIP2 is a cell membrane lipid, and its role in gating ion channels represents a novel role for the molecule. [1] [2]

Kir channels: PIP2 binds to and directly activates inwardly rectifying potassium channels (Kir). [3] The lipid binds in a well-defined ligand binding site in the transmembrane domain and causes the helices to splay opening the channel. All members of the Kir super-family of potassium channels are thought to be directly gated by PIP. [1]

Kv7 channels: PIP2 binds to and directly activates Kv7.1. [4] In the same study PIP2 was shown to function as a ligand. When the channel was reconstituted into lipid vesicles with PIP2 the channel opened, when PIP2 was omitted the channel was closed. [4]

TRP channels: TRP channels were perhaps the first class of channels recognized as lipid-gated. [5] PIP2 regulates the conductance of most TRP channels either positively or negatively. For TRPV5, binding of PIP2 to a site in the transmembrane domain caused a conformational change that appeared to open the conduction pathway, [6] suggesting the channel is classically lipid-gated. A PIP2 compatible site was found in TRPV1 but whether the lipid alone can gate the channels has not been shown. [2] Other TRP channels that directly bind PIP2 are TRPM8 and TRPML. [7] [8] Direct binding does not exclude PIP2 from affecting the channel by indirect mechanisms.

PA-gated channels

Phosphatidic acid (PA) recently emerged as an activator of ion channels. [9]

K2p: PA directly activates TREK-1 potassium channels through a putative site in the transmembrane domain. The affinity of PA for TREK-1 is relatively weak but the enzyme PLD2 produces high local concentration of PA to activate the channel. [10] [11]

nAChR: PA also activates the nAChR in artificial membranes. Initially, the high concentration of PA required to activate nAChR [12] suggested a related anionic lipid might activate the channel, however, the finding of local high concentration of PA activating TREK-1 may suggest otherwise.

Kv: PA binding can also influence the midpoint of voltage activation (Vmid) for voltage-activated potassium channels. [13] Depletion of PA shifted the Vmid -40 mV near resting membrane potential which could open the channel absent a change in voltage suggesting these channels may also be lipid-gated. PA lipids were proposed to non-specifically gated a homologous channel from bacteria KvAP, [14] but those experiments did not rule out the anionic lipid phosphatidylglycerol from contributing specifically to gating.

PG-gated channels

Phosphatidylglycerol(PG) is an anionic lipid that activates many channels including most of the PA activated channels. The physiological signaling pathway is not well studied, but PLD can produce PG in the presence of glycerol [15] suggesting the same mechanism that is thought to generate local PA gradients could be generating high local PG gradients as well.

PC-gated channels

GLIC: The lipid phosphatidylcholine (PC) binds to the outer leaflet of the gleobacter ligad-gated ion channel (GLIC and opens. General anesthetic propofol binds to the same region of the protein as PC. [16] The competition of propofol with the lipid, i.e. displacement of the lipid, is thought to inhibit the channel. [17]


Mechanosensitive channels

A specialized set of mechanosensitive ion channels is gated by lipid deformation in the membrane in response to mechanical force. A theory involving the lipid membrane, called "force from lipid", is thought to directly open ion channels. [18] These channels include the bacterial channels MscL and MscS which open in response to lytic pressure. Many mechanosensitive channels require anionic lipids for activity. [19]

Channels can also respond to membrane thickness. An amphipathic helix that runs along the inner membrane of TREK-1 channels is thought to sense changes in membrane thickness and gate the channel. [20]

PEth is a phospholipid metabolite of ethanol that builds up in the membrane of nerves and competitively inhibits PIP2 activation of K+ channels. PEth competition.png
PEth is a phospholipid metabolite of ethanol that builds up in the membrane of nerves and competitively inhibits PIP2 activation of K+ channels.

Activation by localized lipid production

When an enzyme forms a complex with a channel it is thought to produce ligand near the channel in concentrations that are higher than the ligand in bulk membranes. [10] Theoretical estimates suggest initial concentration of a signaling lipid produced near an ion channel are likely millimolar; [9] however, due to theoretical calculations of lipids diffusion in a membrane, the ligand was thought to diffuse away much to fast to activate a channel. [21] However, Comoglio and colleagues showed experimentally that the enzyme phospholipase D2 bound directly to TREK-1 and produced the PA necessary to activate the channel. [10] The conclusion of Comoglio et al was experimentally confirmed when it was shown that the dissociation constant of PA for TREK-1 is 10 micro molar, [11] a Kd much weaker than the bulk concentration in the membrane. Combined these data show that PA must be local in concentration near 100 micro molar or more, suggesting the diffusion of the lipid is somehow restricted in the membrane.

Activation by membrane protein translocation

In theory, ion channels can be activated by their diffusion or trafficking to high concentrations of a signaling lipid. [9] The mechanism is similar to producing local high concentrations of a signaling lipid, but instead of changing the concentration of the lipid in the membrane near the channel, the channel moves to a region of the plasma membrane that already contains high concentrations of a signaling lipid. The change the channel experiences in lipid composition can be much faster and without any change in the total lipid concentration in the membrane.

Lipid competition

Anionic lipids compete for binding sites within ion channel. Similar to neurotransmitters, competition of an antagonist reverses the effect of an agonist. In most cases, the PA has the opposite effect of PIP2. [9] Hence when PA binds to a channel that is activated by PIP2, PA inhibits the effect of PIP2. When PA activates the channel, PIP2 blocks the effect of PA inhibiting the channels.

Ethanol When ethanol is consumed, phospholipase D incorporates the ethanol into phospholipids generating the unnatural and long lived lipid phosphatidylethanol(PEth) in a process called transphoshatidylation. The PEth competes with PA and the competition antagonizes TREK-1 channels. The competition of PEth on potassium channel is thought to contribute to the anesthetic effect of ethanol and perhaps hangover. [22]

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

<span class="mw-page-title-main">Phosphoinositide phospholipase C</span>

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Palmitoylation</span>

Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (S-palmitoylation) and less frequently to serine and threonine (O-palmitoylation) residues of proteins, which are typically membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their membrane association. Palmitoylation also appears to play a significant role in subcellular trafficking of proteins between membrane compartments, as well as in modulating protein–protein interactions. In contrast to prenylation and myristoylation, palmitoylation is usually reversible (because the bond between palmitic acid and protein is often a thioester bond). The reverse reaction in mammalian cells is catalyzed by acyl-protein thioesterases (APTs) in the cytosol and palmitoyl protein thioesterases in lysosomes. Because palmitoylation is a dynamic, post-translational process, it is believed to be employed by the cell to alter the subcellular localization, protein–protein interactions, or binding capacities of a protein.

Light-gated ion channels are a family of ion channels regulated by electromagnetic radiation. Other gating mechanisms for ion channels include voltage-gated ion channels, ligand-gated ion channels, mechanosensitive ion channels, and temperature-gated ion channels. Most light-gated ion channels have been synthesized in the laboratory for study, although two naturally occurring examples, channelrhodopsin and anion-conducting channelrhodopsin, are currently known. Photoreceptor proteins, which act in a similar manner to light-gated ion channels, are generally classified instead as G protein-coupled receptors.

<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

<span class="mw-page-title-main">KCNK2</span> Protein-coding gene in the species Homo sapiens

Potassium channel subfamily K member 2, also known as TREK-1, is a protein that in humans is encoded by the KCNK2 gene.

The G protein-coupled inwardly rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs in turn release activated G-protein βγ- subunits (Gβγ) from inactive heterotrimeric G protein complexes (Gαβγ). Finally, the Gβγ dimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell membrane. G protein-coupled inwardly rectifying potassium channels are a type of G protein-gated ion channels because of this direct interaction of G protein subunits with GIRK channels. The activation likely works by increasing the affinity of the channel for PIP2. In high concentration PIP2 activates the channel absent G-protein, but G-protein does not activate the channel absent PIP2.

Mechanosensation is the transduction of mechanical stimuli into neural signals. Mechanosensation provides the basis for the senses of light touch, hearing, proprioception, and pain. Mechanoreceptors found in the skin, called cutaneous mechanoreceptors, are responsible for the sense of touch. Tiny cells in the inner ear, called hair cells, are responsible for hearing and balance. States of neuropathic pain, such as hyperalgesia and allodynia, are also directly related to mechanosensation. A wide array of elements are involved in the process of mechanosensation, many of which are still not fully understood.

Mechanosensitive channels (MSCs), mechanosensitive ion channels or stretch-gated ion channels are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.

Substrate presentation is a biological process that activates a protein. The protein is sequestered away from its substrate and then activated by release and exposure of the protein to its substrate. A substrate is typically the substance on which an enzyme acts but can also be a protein surface to which a ligand binds. The substrate is the material acted upon. In the case of an interaction with an enzyme, the protein or organic substrate typically changes chemical form. Substrate presentation differs from allosteric regulation in that the enzyme need not change its conformation to begin catalysis. Substrate presentation is best described for domain partitioning at nanoscopic distances (<100 nm).

<span class="mw-page-title-main">Cholesterol signaling</span>

Cholesterol is a cell signaling molecule that is highly regulated in eukaryotic cell membranes. In human health, its effects are most notable in inflammation, metabolic syndrome, and neurodegeneration. At the molecular level, cholesterol primarily signals by regulating clustering of saturated lipids and proteins that depend on clustering for their regulation.

PIP2 domains are a type of cholesterol-independent lipid domain formed from phosphatidylinositol and positively charged proteins in the plasma membrane. They tend to inhibit GM1 lipid raft function.

<span class="mw-page-title-main">GsMTx-4</span> Grammostola mechanotoxin 4

Grammostola mechanotoxin #4, also known as M-theraphotoxin-Gr1a (M-TRTX-Gr1a), is a neurotoxin isolated from the venom of the spider Chilean rose tarantula Grammostola spatulate. This amphiphilic peptide, which consists of 35 amino acids, belongs to the inhibitory cysteine knot (ICK) peptide family. It reduces mechanical sensation by inhibiting mechanosensitive channels (MSCs).

Membrane-mediated anesthesia or anaesthesia (UK) is a mechanism of action that involves an anesthetic exerting its effects through the lipid membrane. Established mechanism exists for both general and local anesthetics. The anesthetic binding site is within ordered lipids and binding disrupts the function of the ordered lipid. See Theories of general anaesthetic action for a broader discussion of purely theoretical mechanisms.

References

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  12. ↑ Hamouda AK, Sanghvi M, Sauls D, Machu TK, Blanton MP (April 2006). "Assessing the lipid requirements of the Torpedo californica nicotinic acetylcholine receptor". Biochemistry. 45 (13): 4327–37. doi:10.1021/bi052281z. PMC   2527474 . PMID   16566607.
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