Home NEUR 310 Thursday, March 13, 2014

Thursday, March 13, 2014 CC-BY-NC
Neurotransmitters

Maintainer: admin

1Neurotransmitter

  • classical versus peptide transmitters:

    • by the way they're synthesized
    • classical: synthesized in cytoplasm and packaged into synaptic vesicles by transporters
      • Glutamate, GABA, glycine, amino-acid transmitters
        • does both fast and slow neurotransmission
      • biogenic amines: dopmaine, serotonin, adrenaline, histamine
      • Ach is in both classes
        • act as fast transmitter in muscles
        • ats as biogenic amine in brain
    • peptide transmitters: synthesized by translation of mRNA and packaged into secretory (dense core) vesicles)

  • slow versus fast neurotransmission

    • fast: ligand-based ion channels, by classical neurotransmitters
    • slow: via G-protein linked receptors, mediated by both types of neurotransmitters
      • neuropeptides are released from outside of the active zone, where classical transmitters are released

1.1Amino-acid based transmitters

  • 90% of neurons in brain: glutmate (excitatory) and GABA (inhibitory)
  • acytocholine (Ach) : both fast and slow, limited by choline acetyltransferase
  • glutamate : both fast and slow, limited by glutamate vesicular transporter
    • made by almost all neurons
  • GABA : both fast and slow, limited by glutamic acid decarboxylase,
    • made by only inhibitory neurons

  • glycine: only fast, limited by glycine plasma membrane transporter, inhibitory

  • ATP: boh fast and slow, often a co-transmitter

1.2Biogenic amines

  • localized in mid-brain nuclei

  • dopamine : slow, limited by tyrosine hydroxylase (TH)

    • lost in Parkinson disease
    • made in Substantia niagra, etc
  • norepinephrine : slow, made from dopamine + beta-hydroxylase
    • in Locus Coeruleus
  • epinephrine : slow, made from norepinephrine + PNMT
    • in adrenal medula
  • serotonin : slow, limited by tryptophan hydrolase
    • in raphe nucleus
  • histamine : slow, limited by histidine decarboxylase,
    • in hypothalamus

2Using neurotransmitter

  • each neuron uses only one classical transmitter, but several neuropeptides

  • neurons require

    • (always) a vesicle tranporter to concentrate the transmitter into a vesicle
    • (somtimes)
      • way to degrade the transmitter
      • reuptake transporter for the transmitter
      • enzymes to synthesie the neurotransmitters

  • vescle transporter

    • use ATPs to pump H+ into the vesicle and then use the H+ gradience to concentrate transmitters
    • two types
      • plama membrane transporters : from extracellular space to cytosol
      • vesicular transporters : from cytosol to vesicle
    • all have 12 transmembrane (TM) regions

    • are not like channels

    • only four classes

      • Vesicular monoamine transporter (VMAT): all biogenic amines
      • vesicular acetylcholine transporter (VAchT): in intron of choline acetyltransferase gene
      • Vesicular GABA and glycine transporter (VgaT): rate limitnig for glycine transport
      • vesicular glutamate transporter (VgluT) : 3 isoforms
        • 1 and 2 : glutaminergic cells
        • 3: GABA or serotonin-releasing cells, lack of it leads to deafness

2.1Vglut3

  • put VgluT in GABA neurons: probably would let that neurons release glutamate

  • increase number of VgluT : may lead to increased glutamate stored in a synaptic vesicle

    • thus larger EPSP
    • when VgluT is limiting, more vesicles with transmitters are formed

  • if synaptic vesicles formed without transporter : probably empty vesicles

  • Vglut3 allow co-release

    • in dopaminergic neurons, it allow co-release of dopamine and gluamate
    • in autditory cortex: co-release of glutamate and GABA

  • VAchT and VgluT3 on the same syanptic vesicles in striatum

    • adding glutamate increase Ach uptake into striatal Ach vesicles
    • VgluT is also important for serotonin release in some terminals
    • this is believed to be due to glutamate help balancing the charges in vesicles
      • glutamate is negative, so it lower the charge gradeitn and enable ATP pump to work better pumping H+ into the vesicles

3Synthesic pathways

  • choline -> (choline acetyl transferase) -> acetycholine (Ach)
  • tyrosine -> (tyrosine hydroxylase) -> L-DOPA
    • L-DOPA: used to treat Parkinson disease because it crosses BBB and become dopamine
    • tyrosine hydroxylase : rate limiting so highly regulated
  • L-DOPA -> (Dopa-decarboxyalse) -> Dopamine
  • Dopamine -> (dopamine b-hydroxylase in vesicles) -> norepinephrine
    • unlike all other biosynthetic enzymes which are in cytosol

3.1Regulaion

  • regulate rate-limiting enzyme
  • phosphorylation of rate limiting enzyme
  • feedback: cells sense absence of transmitter and increase synthesis

4Removal of transmitters

  • for fast transmission : to make sure each signal is distinct since information depends on frequency of signals.
  • for slow transmission : to regulate responses and amount of release

  • methods

    • degradation : like acetycholinesterase and monoamine oxidase (degrade biogenic amines)
    • reuptake :
      • glutamate uptake by glial cells, which turn glutamate into glutamine, and then released it. Neurons then take up glutamine and turn it into glutamate for release
      • GABA : taken up by both neurons and glial cells
      • major source of transmitters
      • uses A LOT of energy
        • ~30% of energy used in brain is for supporting glutamate-glutamine cycle
        • use of glucose to support transmitter recycling : basis fo fMRI

  • blockage of biogenic amine trnasporters is a therpeutic targets for many drugs

5Review

  • two classes of classical transmitters: amino acids based and biogenic amines
    • we'll talk about neuropetide in another lecture
  • biosynthesis is based on enzymetic reaction and transport into synaptic vesicle
  • removal is also important for regulation