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.

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. [16] These channels include the bacterial channels MscL and MscS which open in response to lytic pressure. Many mechanosensitive channels require anionic lipids for activity. [17]

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. [18]

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. [19] 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. [20]

Related Research Articles

Ion channel

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.

Potassium is the main intracellular ion for all types of cells, while having a major role in maintenance of fluid and electrolyte balance. Potassium is necessary for the function of all living cells, and is thus present in all plant and animal tissues. It is found in especially high concentrations within plant cells, and in a mixed diet, it is most highly concentrated in fruits. The high concentration of potassium in plants, associated with comparatively very low amounts of sodium there, historically resulted in potassium first being isolated from the ashes of plants (potash), which in turn gave the element its modern name. The high concentration of potassium in plants means that heavy crop production rapidly depletes soils of potassium, and agricultural fertilizers consume 93% of the potassium chemical production of the modern world economy.

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 tastes, 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.

Ligand-gated ion channel Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

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.

Inward-rectifier potassium channel

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.

Phosphatidylinositol 4,5-bisphosphate 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.

Phospholipase D (PLD) is an enzyme of the phospholipase superfamily. Phospholipases occur widely, and can be found in a wide range of organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase D's principal substrate is phosphatidylcholine, which it hydrolyzes to produce the signal molecule phosphatidic acid (PA), and soluble choline in a cholesterol dependent process called substrate presentation. Plants contain numerous genes that encode various PLD isoenzymes, with molecular weights ranging from 90 to 125 kDa. Mammalian cells encode two isoforms of phospholipase D: PLD1 and PLD2. Phospholipase D is an important player in many physiological processes, including membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, and cell migration. Through these processes, it has been further implicated in the pathophysiology of multiple diseases: in particular the progression of Parkinson's and Alzheimer's, as well as various cancers. PLD may also help set the threshold for sensitivity to anesthesia and mechanical force.

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.

TRPV2

Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.

Cation channel superfamily Family of ion channel proteins

The transmembrane cation channel superfamily was defined in InterPro and Pfam as the family of tetrameric ion channels. These include the sodium, potassium, calcium, ryanodine receptor, HCN, CNG, CatSper, and TRP channels. This large group of ion channels apparently includes families 1.A.1, 1.A.2, 1.A.3, and 1.A.4 of the TCDB transporter classification.

Phospholipase C 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.

KCNK2

Potassium channel subfamily K member 2 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, mechanosensitive ion channels or stretch-gated ion channels (not to be confused with mechanoreceptors). 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.

This is a list of articles on biophysics.

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 nanoscopic distances (<100 nm).

Cholesterol signaling

Cholesterol is a 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 (e.g.,) and positively charged proteins in the plasma membrane. They tend to inhibit GM1 lipid raft function.

References

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  2. 1 2 Gao Y, Cao E, Julius D, Cheng Y (June 2016). "TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action". Nature. 534 (7607): 347–51. Bibcode:2016Natur.534..347G. doi:10.1038/nature17964. PMC   4911334 . PMID   27281200.
  3. ↑ Hansen SB, Tao X, MacKinnon R (August 2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2". Nature. 477 (7365): 495–8. Bibcode:2011Natur.477..495H. doi:10.1038/nature10370. PMC   3324908 . PMID   21874019.
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  5. ↑ Benham, CD; Davis, JB; Randall, AD (June 2002). "Vanilloid and TRP channels: a family of lipid-gated cation channels". Neuropharmacology. 42 (7): 873–88. doi:10.1016/s0028-3908(02)00047-3. PMID   12069898. S2CID   29312985.
  6. ↑ Hughes TE, Pumroy RA, Yazici AT, Kasimova MA, Fluck EC, Huynh KW, et al. (October 2018). "Structural insights on TRPV5 gating by endogenous modulators". Nature Communications. 9 (1): 4198. Bibcode:2018NatCo...9.4198H. doi:10.1038/s41467-018-06753-6. PMC   6179994 . PMID   30305626.
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  8. ↑ Yin Y, Le SC, Hsu AL, Borgnia MJ, Yang H, Lee SY (March 2019). "Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel". Science. 363 (6430): eaav9334. doi:10.1126/science.aav9334. PMC   6478609 . PMID   30733385.
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  10. 1 2 3 Comoglio Y, Levitz J, Kienzler MA, Lesage F, Isacoff EY, Sandoz G (September 2014). "Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid". Proceedings of the National Academy of Sciences of the United States of America. 111 (37): 13547–52. Bibcode:2014PNAS..11113547C. doi: 10.1073/pnas.1407160111 . PMC   4169921 . PMID   25197053.
  11. 1 2 Cabanos C, Wang M, Han X, Hansen SB (August 2017). "2 Antagonism of TREK-1 Channels". Cell Reports. 20 (6): 1287–1294. doi:10.1016/j.celrep.2017.07.034. PMC   5586213 . PMID   28793254.
  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.
  13. ↑ Hite RK, Butterwick JA, MacKinnon R (October 2014). "Phosphatidic acid modulation of Kv channel voltage sensor function". eLife. 3. doi:10.7554/eLife.04366. PMC   4212207 . PMID   25285449.
  14. ↑ Zheng H, Liu W, Anderson LY, Jiang QX (22 March 2011). "Lipid-dependent gating of a voltage-gated potassium channel". Nature Communications. 2 (1): 250. Bibcode:2011NatCo...2..250Z. doi:10.1038/ncomms1254. PMC   3072105 . PMID   21427721.
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  16. ↑ Teng J, Loukin S, Anishkin A, Kung C (January 2015). "The force-from-lipid (FFL) principle of mechanosensitivity, at large and in elements". Pflügers Archiv. 467 (1): 27–37. doi:10.1007/s00424-014-1530-2. PMC   4254906 . PMID   24888690.
  17. ↑ Powl AM, East JM, Lee AG (April 2008). "Anionic phospholipids affect the rate and extent of flux through the mechanosensitive channel of large conductance MscL". Biochemistry. 47 (14): 4317–28. doi:10.1021/bi702409t. PMC   2566799 . PMID   18341289.
  18. ↑ Nayebosadri A, Petersen EN, Cabanos C, Hansen SB (2018). "A Membrane Thickness Sensor in TREK-1 Channels Transduces Mechanical Force". doi:10.2139/ssrn.3155650.{{cite journal}}: Cite journal requires |journal= (help)
  19. ↑ Hilgemann DW (October 2007). "Local PIP(2) signals: when, where, and how?". Pflügers Archiv. 455 (1): 55–67. doi:10.1007/s00424-007-0280-9. PMID   17534652. S2CID   29839094.
  20. ↑ Chung HW, Petersen EN, Cabanos C, Murphy KR, Pavel MA, Hansen AS, et al. (January 2019). "A Molecular Target for an Alcohol Chain-Length Cutoff". Journal of Molecular Biology. 431 (2): 196–209. doi:10.1016/j.jmb.2018.11.028. PMC   6360937 . PMID   30529033.
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