Modulating Membranes

• Neurotransmitters


  Chemicals that modulate resting membrane potential to take it closer to the threshold (depolarisation/excitation), or further away (hyperpolarization/inhibition)
• Information conveyed from neuron to neuron

  1. Chemical

  2. Electrical messages across synapse
• Chemical


  Chemicals (neurotransmitters) are released from vesicles that travel across synapses and then bind to post-synaptic receptors
• Ionotropic


  Ligand-gated channels
• Main classes of neurotransmitters

  • Small-molecule neurotransmitters
  • Amines
  • Peptides
• Synaptic inputs result in graded changes in membrane potential
• Synaptic inputs can be mediated by chemical or electrical connections
• Main classes of receptors

  • Ionotropic
  • Metabotropic
• Fast neuronal regulation is produced by ionotropic receptors
• Glutamate


  The principal fast excitatory neurotransmitter
• Ionotropic receptors (ion channels)


  • 3 different classes classified based on their pharmacology
  • Subunits within these classes are determined by their genes
• Subunit


  Contains an amino terminus, transmembrane spanning domain, carboxy terminus
• Formation of receptor pore/channel

  1. Multiple subunits are put together

  2. Usually, glutamate receptors have 4 subunits (sometimes 5)

  3. Different receptors can be made by different subunit combinations
• AMPA receptor


  The predominant ion that will move across the membrane when glutamate binds is Na+, flowing into the cells
• NMDA receptor


  • Glutamate binding opens a channel that transmits Ca2+, K+ and Na+
  • There is an Mg2+ ion that sits within the channel to block the ion channel when open, so the Mg2+ needs to be removed for ion flow to occur
  • For the Mg2+ to be removed depolarisation of the neuron had to occur
  • Both ligand and voltage-dependent
• AMPA and NMDA receptors working together

  1. Glutamate binds to AMAP receptor leading to depolarisation as Na+ flows into the cell

  2. This then enables the glutamate to bind to the NMDA receptor to open the channel and Mg2+ to be removed
• Glutamate ionotropic receptors are non-selective cation channels
• Glutamate ion channel families

  • AMPA
  • Kainate
  • NMDA
• Glutamate ion channels


  • Channels are made up of subunits which have three membrane-spanning domains and a re-enterant loop
  • Most models predict 4 subunits making it an ion channel
• Opening of AMPA receptors following the binds of glutamate results in the rapid opening of the channel creating short-duration changes in the current flow
• Recycling of neurotransmitters


  1. Glutamate can be removed, recycled, repackaged and then reused

  2. There are 3 versions of VLGUT (= vesicular glutamate transporter) that package glutamate into vesicles

  3. EATT (excitatory amino acid transporters) rapidly remove glutamate from the synaptic cleft and move it to glial cells where it is converted to glutamine

  4. Glutamine is then transported back to the neuron where glutaminase converts it back into glutamate
• Acetylcholine receptors


  • Can be ionotropic receptors
  • Non-selective cation channels
  • Constructed from 4 transmembrane-spanning subunits (alpha, beta, gamma and delta)
• Muscarinic receptors


  Metabotropic or GPCR
• Nicotinic receptors


  • Important for somatic motor movement
  • Target for many toxins
• Acetylcholine inactivation


  1. Acetylcholinesterase breaks down Ach to acetate and choline

  2. Acetate is broken down

  3. Choline is recycled by Na+/choline receptors
• Acetylcholine is another key fast ionotropic neurotransmitter, it acts via nicotinic acetylcholine receptors
• Nicotinic receptors are also non-selective cation channels
• Nicotinic receptors are made of pentamer of four transmembrane-spanning domains
• Acetylcholine is rapidly metabolised in the synapse by the enzyme, acetylcholinesterase
• Electrical synapses


  • Physical connection via gap junctions
  • Ions can move along electrochemical gradients and can be bidirectional
• Connexon


  Made up of 6 connexins and each of the 6 connexins has 4 membrane-spanning regions
• Gap junctions


  Can be used for communication of other small molecules between pre and post-synaptic neurons e.g. calcium, ATP etc (there is a size cut-off)
• Mixed synapse


  Chemical and electrical together
• Electrical synapses enable the direct passage of ions between neurons
• Electrical synapses alter the postsynaptic membrane potential
• Gap junctions, composed of molecules such as connexins, enable electrical synapses
• Many synapses consist of both chemical and electrical synapses
• Core concepts


  • Receptors transduce transmitter input into altered membrane potential
  • Receptors are transmembrane-spanning proteins that have highly specific ligand-binding domains
  • Ionotropic receptors are made up of collections of protein subunits that interact to form a pore
  • Many ionotropic receptor ion channels are not selective for a particular ion and do not determine the direction of ion movement - the effect of opening the channel is dependent upon the membrane potential and the transmembrane ion concentrations
  • Fast transmission requires fast removal of the stimulus either by ligand uptake or degradation