Lecture 9: Ion Channel Function Flashcards
Where this is Going = 5
1 ➢Neural and muscle function depends on ion channels
2 ➢Opening voltage gated channels allows action
potentials
3 ➢Opening of voltage gate calcium channels allows release of neurotransmitters and contraction of muscle
4 ➢Opening of ligand gate ions channels allows reception of neurotransmitter signals.
5 ➢Sensory systems all rely on ion channels
Ion Channels = 5
1 ➢Ion channels can be made up of SAME SUBUNITS (PROTEINS) or can be an assembly of different proteins
2 ➢ Allow LIPOPHOBIC ions to travel through lipid membrane
3 ➢Ion channels are SELECTIVE for specific ions
4 ➢Most ion channels are GATED, can be opened and
closed
5 ➢Movement of ions is PASSIVE
Ion Channel Structure (PROTEINS) = 4
- Primary structure – sequence of amino acids
- Secondary structure – alpha helix
- Tertiary structure – 3D folding of
polypeptide - Quaternary structure – different polypeptides bonded together
Ion Channel Structure =
Structure of membrane spanning protein 2
- Membrane spanning -helices contain hydrophobic amino acid residues.
- Connected by loops of hydrophilic residues.
Ion Channel Structure = Typical structure of voltage-gated Na+ channel
- 4 domains containing 6 x membrane spaning hydrophobic ALPHA- helices.
- Aqueous pore formed by one of the ALPHA-helices.
- Another ALPHA-helix (S4) contains the voltage sensor.
Ion Channel Diversity
- Due to availability many different subunits
TYPES
- HETEROOLIGOMERS, HOMOOLIGOMERS, (IN SINGLE POLYPEPTIDE CHAIN) AND AUXILLARY SUBUNITS
HETEROOLIGOMERS
Distinct subunits
(IN SINGLE POLYPEPTIDE CHAING)
HOMOOLIGOMERS
single subunits(IN SINGLE POLYPEPTIDE CHAING)
Ion Channel Selectivity =
Selectively permeable Selectivity determined by: 3
1 * Sizeofpore
2 * Electrical charges of chains of amino acids that enter the pore
- EXAMPLE: Na+ channels Selectivity filter weakly binds Na+ ions.
- charge stabilised by a hydrophilic amino acid
UNDERSTANDING ION CHANNEL SELECTIVITY = 7
1 ➢ Selection by charge, negative charged throat repels anions makes the channel cation selective.
2 ➢ Selection by ion size, small throat will not let large ions through.
3 ➢ Easy to see how a channel can let Na+ but not the larger K+ or the anion Cl- through.
4 ➢ How do K+ channels keep the smaller cation Na+ out?
5 ➢ In solution ions have hydrogen bonds to water, the hydrated
shell.
6 ➢ Most hydrogen bonds to water replaced by bonds to channel amino acids.
7 ➢ Na+ is too small to hydrogen bond to both sides of the channel but too big to fit when bonded to water.
UNDERSTANDING Ion Channels Gating
- Patch-clamp setup:
Records current flow from a single ion channel - All or nothing opening of variable duration, but constant amplitude
Ion channel opening is not
determinant but stochastic (opening probability)
GATING TYPES = 4
- LIGAND GATED
- VOLTAGE GATED
- MECHANICALLY GATED
- COVALENT MODIFICATION
LIGAND GATES
Requires binding of a chemical e.g. a transmitter
VOLTAGE GATES
Requires a voltage change across the membrane
MECHANICAL GATES
Requires stretching or some displacement
Ligand Gated channels = DIRECT 3
- Channel opens in response to binding of the ligand to receptor.
- The ligand is called an AGONIST
- May be neurotransmitters or hormones, usually bind on extracellular side of channel.
Antagonist
- can inhibit binding of endogenous ligand.
-LIGAND GATED CHANNELS
Types of Ligands Gated Channels = Antagonist
- Curare – blocks nicotinic ACh receptor.
- Lidocaine - local anaesthetic, binds to domain IV of Na+ channel. Inhibits AP generation.
- Tetrodotoxin (TTX; found in puffer fish) binds to voltage gated Na+ channels preventing AP generation. Fatal
Ligand Gated Channels - INDIRECT -2
- Channel opens in response to a second messenger signal activated by a neurotransmitter.
- Second messenger (eg G-PROTEIN) acts on the intracellular side of the channel – couples the receptor to the ion channel
Voltage Gated Channels
- Change in membrane voltage can open and close some channels.
- Detects changes in the electrical potential across the membrane.
outside (+), Inside (-) —–>. Change (transmembrane potential)—> outside (-), Inside (+)
Inactivation Gate:
Opening vs Inactivation
- Opening
- Conformational change occurs in one region of the channel - Inactivation
- Blocking particle swings into and out of channel mouth
Multiple Confirmation States
3 states of Na+ channels
- Resting - closed & activatable
- Activated - open
- Inactivated - closed and non-activatable
what happens during resting stage in voltage gate
activation gate closed
inactivation gate open