Ion channels


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Ion channels

  1. 1. Little appreciated fact of physiology Human beings (and other living organisms) are run by electricity, and "ion channels" are the core of our electrical system Ion channelsIon channels Ion channels Yet another type of membrane transport Small highly selective pores in the cell Pores in the membrane that open and close in a membrane regulated manner and allow passage of ions Move ions or water “Dispose” of the gradients Fast rate of transport 107 ions/s Passive transporters Transport is always down the gradient Ions flow from high to low concentration Can not be coupled to the energy source No energy is used If there is no gradient ions will not flowIon channels are everywhere Ion channels function Channels are present in almost every cell Responsible for processes such as Functions Heart beat Transport of ions and water Muscle contraction Regulation of electrical Hormone secretion potential across the Vision and olfaction membrane Pain Signaling Cognition And pretty much everything else
  2. 2. Channel proteins Genetics of ion channels Integral membrane proteins Product of many genes Multiple transmembrane domains (2-24) Emerged from very few Multiunit complexes primordial genes through Form water filed pores duplication and divergence Not always open = different gating mechanisms Homology based on Many diverse families general structural features rather than ion selectivityGenetics of ion channels KcsA channel Major cation channel families belong to S5/S6 Bacterial K+ channel group Four subunits All contribute to ion poreK+ movement through the pore Selectivity filter Helix dipoles of the pore helices produce a cloud Transmembrane helices are of negative charge which attracts the K+ ions into close together on the the water filled cavity in the center cytoplasmic side Ions bind inside the pore Form ion “sieve” – perfect fit In very selective channels dehydrated ion passes through the hole
  3. 3. Selectivity Regulation of channel activity Determined by an ion pore Long term – expression (means simply number Mutation in a pore region changes selectivity and type of channels on the cell) Change from negative to positive charge within the pore Cells express different set of channel protein will change a channel from cation to anion selective depending on the function Selective (discriminate between very similar ions Expression can be regulated by growth factors, inflammatory mediators, hormones) such as Na+ and K+) Short term – gating (how long is channel open) Non-selective (but still transport anions or cations, never both)Gating mechanisms What gates ion channels? Two discrete states – open Non gated - always open (conducting) or closed Gated (nonconducting) Voltage across the cell membrane Some channels have also Ligand inactivated state (open but Mechanical stimulus, heat (thermal fluctuations) nonconducting) Part of the channel structure or external particle blocks otherwise open channelGating mechanisms Single channel function Conformational changes in channel protein are Binary – conducting or nonconducting responsible for opening and closing of the pore Transition is instantaneous 3D conformational shape is determined by atomic, Channels fluctuate between open and closed electric, and hydrophobic forces state on a millisecond timescale Energy to switch the channel protein from one conformational shape to another comes from the gating source
  4. 4. Channels with four transmembraneSingle channel function segments TWIK Function is encoded by the time a channel spends Four transmembrane segments and two P loops in an open state Resting or “leak” K+ channels this decides how much current flows through Always open Transition between states is regulated by external Help establish membrane potential stimuli G proteins Phosphorylation Interaction with the receptorsChannels with six transmembranesegments Voltage-gated cation channels The remnant of S5/S6 family Open in response to changes in membrane Voltage gated cation channels potential Potassium Subsequently open and inactivate Sodium Specific for a particular ion Calcium Common domain structure Voltage gated chloride channels Regulated by external signals Channels gated by intracellular ligands (such as cGMP gated channels in rods and cones of a retina)Voltage-gated cation channels - Voltage-gated cation channels -function structure Na+ and K+ Contain four subunits each containing six Action potential transmembrane segments Ca2+ K+ is a tetramer Secretion Na+ and Ca2+ 4 polypeptides are connected into one chain Signaling Muscle contraction Gene expression
  5. 5. Voltage-gated cation channels -structure Voltage sensor S5 and S6 and P loop between them form Positively charged AA (lysine or arginine) every selectivity filter third residue in S4 S4 forms a voltage sensor This part of the channel is attracted to the negative voltage Resting potential - negative inside voltage sensor deep in the membrane Action potential – reversal of charges voltage sensor moves upHow does the Na+ channel open and Ball and chain mechanism ofclose? inactivation Part of the channel protein forms inactivation peptide Channel must open first to be inactivated• In response to voltage change S4 rotates and moves toward exterior of the cellVoltage - gated Na+ channels Voltage - gated Ca2+ channels One large polypeptide of four domains One large polypeptide of four domains Responsible for depolarization phase of action Heavily regulated by cell surface receptors potential Have the place for the direct interaction with G Target for local anesthetics proteins and phosphorylation Inactivation Responsible for ALL secretion Presynaptic terminal and all secretory cells
  6. 6. Voltage-gated Ca2+ channels The rest of the bunch In neurons mostly responsible for the entry of Ligand gated channels calcium into the presynaptic ending following Glutamate receptors depolarization (and subsequent exocytosis of Nicotinic acetylcholine receptor neurotransmitter) Vanilloid receptor family (TRPV) In heart excitation contraction coupling In all excitable secretory cells (adrenal medulla, pancreas) entry of calcium induces secretionLigand gated ion channels Glutamate receptors Gated by ligands present outside of the cell Two major groups In fact they are receptors NMDA All of them are nonselective cation channels AMPA (kainate) Mediate effects of neurotransmitters Both implicated in learning and memoryAquaporins or water channels Aquaporins or water channels Tetramers with four identical subunits Six membrane domains in each subunit Each with a water pore Two halves of the polypeptide are identical and Predominantly expressed in cells that express reversed high permeability to water (erythrocytes, kidney) Different tissues express different isoforms Hormone vasopressin increases expression of aquaporins in collecting duct membranes
  7. 7. When ion channels fail to function“Killer” channels normally… Gramicidin A A number of diseases can occur Bacteria produces small peptides that when Epilepsy inserted into the membrane of other cells form Deafness highly selective K+ channels Blindness Escaping K+ changes transmembrane potential Migraine headaches and kills the cell Cardiac arrhythmias Deregulation of cognitive dysfunction, as in Alzheimers disease