L4 - Ion Channels

• Ligand gated ion channels also called ionotropic receptors
• • Ligand = message/signal → small molecule that binds to a large one; they change ion composition of cell
  • A multi-subunit protein that crosses through the plasma membrane
  • Proteins come together to form channel
  • A channel may be closed or open
  • When open ions move into, ot out of, the cell depending on their electrochemical gradient
  • If high conc outside - move inside
  • The type of ion(s) moving through the channel is determined by the channels structure (chemical make-up)
  • Change shape depending what they are
  • Ligand/signal molecule can arrive from inside or outside of cell
• Channels may be opened by different stimuli:

  • Changes in voltage across the membrane (voltage gated)
  • Deformation of the membrane (mechanically gated)
  • When physical pressure is applied
  • Ligands at the cell surface (always open)
  • Opened by (eg neurotransmitter)
  • Note: some channels are always open
• Channels may be opened by different stimuli:

  • A further class of ion channels are opened in response to internal signals
  • Often “downstream” of GPCRs
  • Cause channels to open from inside
  • Include GIRK (G-protein gated inwardly-rectifying potassium channels) which allow K+ go move out of a cell
  • G-protein (𝛽𝑦 subunit) attaches to GIRK
• Ligand-gated Ion Channels:

  • Ligand gated ion channels provide rapid & normally short lasting signals to cells
  • Particularly well suited to signalling in the nervous system
  • Dominant in brain
  • Channels may be modulated by additional factors
• Channels Subunits:

  • Channels are composed of multiple subunits
  • Subunits different to each other
  • 4 to 5, depending on channel type
  • Each protein subunit makes 4 passes across the membrane
• Ligand-gated Ion Channels:

  • Best studied ligand-gated ion channels is the nicotinic acetylcholine receptor at the neuro-muscular junction (NMJ)
  • Bc/ is most important & because they could
  • Made up of 5 subunits
  • Influx of Na+ causes the muscle to depolarise to contract
  • Nicotinic receptors also present in the brain
  • Smoking changes how you feel
  • These have different subunits structures & thus different properties
  • Respond in different ways
  • Vary with brain region & development (get replaced thru development)
• Nicotinic acetylcholine - neuromuscular junction:

  • Like most cellular proteins the nicotinic acetylcholine receptor functions as part of a complex w/ other proteins
  • No protein works on its own, come together to make receptor work
  • Complex involved in correctly maintaining the positioning of the receptor for most effective functioning
  • Nicotinic acetylcholine works as complex (w/ other proteins) & functions as a unit
  • Protein anchors receptor
• Nicotinic acetylcholine - neuromuscular junction:

  • Rapsun concentrates / anchors the nAChR at the correct location opposite the synapse
  • Loss of dystrophin results in Duchenne Muscular Dystrophy, an X-linked muscle wasting disorder
  • Weak connection, low Na+ in
  • Similar protein complexes support the functioning of most receptor types incl ion channels, GPCR & cytokine receptors
  • Proteins anchors receptor
• The relationship between ion channel receptors & protein kinases:

  • Examine synaptic transmission as an example
  • Can be regulated in the cell
  • Ion channels also help protein kinase
• Synaptic Transmission:

  • 2 types of glutamate receptor are present at some synapses
  • AMPA receptors are ion channels that allow Na+ into the post-synaptic target cell
  • NMDA receptors are ion channels that allow Ca2+ into the post-synaptic target cell
  • An increase in Ca2+ can stimulate multiple cellular events include protein kinases
• Synaptic Transmission:

  • Vesicle got glutamate & released & needs to interact with receptor
  • Different sorts of ion channels for it
  • Open & let in sodium
  • Also other type NMDA (named after drugs helped to identify them)
  • Opens let in sodium & calcium
  • Calcium special signal as not much calcium in cell but a lot outside (BANG - rushes inside), turns on protein kinase
  • Protein kinases can now make multiple things happen
• Synaptic Transmission:

  • Activation of these kinases (incl CaMKll) can mediate many intracellular actions
  • CaMKll plays an important role in long term potentiation - a mechanism involved in memory formation
  • Ca2+ dependent kinase
  • Can regulate release of things from that cell
  • Some to nucleus, turn genes on & off, transcription factor
  • Changes neuron, essentially for ever (memory of it), change how behave