metabotropic receptors

Neurotransmitters

Central nervous system

  • Glutamate 
  • GABA 
  • Glycine 
  • Dopamine 
  • Serotonin 
  • Noradrenaline 
  • Histamine 
  • Orexin 
  • Endorphins 

Peripheral nervous system 

  • Noradrenaline 
  • Acetylcholine 

Neurotransmitter synthesis/packaging 

  • Some neurotransmitters are readily available amino acids eg Glutamate, glycine 
  • Some are synthesised by the cells that secrete them eg GABA, noradrenaline, dopamine 

Noradrenaline synthesis:

Packaging

  • In the presynapse, neurotransmitter is contained in vesicles 
  • The neurotransmitter must be packaged into the vesicle ready for release 
  • Uses transporters and proton gradients to package 

[packaging and release - above]

  • Neurotransmitter release is quantal – Each vesicle contains the same amount of neurotransmitter 
  • Therefore it is the number of vesicles fusing which determines the post synaptic potentials 
  • membranes must fuse for release - membrane fusion is energetically unfavourable so must be catalysed by something

SNARE Hypothesis 

  • Proteins on the presynaptic membrane ‘grab’ proteins on the vesicle membrane 
  • These SNARE proteins pull the two membranes close together 
  • SNARE proteins provide most of the energy for membrane fusion
  • v-SNARE (VAMP2) – on vesicle membrane 
  • t-SNAREs (syntaxin1A, SNAP-25) on target membrane 
  • Bind together to make SNARE complex 
  •  SNARE ‘zippering’ forces the membranes close together 
  • Spontaneous, highly energetically favourable 
  • Once assembled, they require ATP hydrolysis to separate them 
  •  Ca2+ binding to synaptotagmin provides extra energy to fuse the membranes

Neurotransmitter release

  • synaptic vesicle release sites are highly organised and regulated
  • exocytose into synaptic cleft

presynaptic active zone:


Neurotransmitter detection

  • Ionotropic (ion channel coupled) – Glutamate, GABA, Glycine 
  • Metabotropic (G-protein coupled) – monoamines, histamine etc. 
  • Some have both kinds, e.g. glutamate, GABA 
  • Ionotropic responses are faster 
  • Metabotropic responses can have more diverse effects 

Glutamate receptors

  • Glutamate is the main excitatory neurotransmitter in the brain 
  • Three classes of ionotropic receptor – AMPA – NMDA – Kainate 
  •  Named after pharmacological agonists 
  • All let in positive ions when they bind glutamate 
  • Glutamate also has a family of metabotropic receptors – mGluRs – These modulate neurotransmission 

AMPA Receptors 

  •  Main fast excitatory receptor 
  • Strength of a synapse is largely determined by its complement of AMPARs
  •  More AMPAR in the post-synaptic membrane = stronger synaptic transmission 

NMDA Receptors 

  • Minor role in postsynaptic firing 
  • Major role is in synaptic plasticity 
  • NMDA receptors are calcium permeable 
  • require strong neurotransmitter release to open 
Drug Receptors - Pharmacology

Ligand-Gated Ion Channels 

  • Ionotropic receptors
  • Structurally similar to other ion channels 
  • Quickest response
  • Each receptor consists of 16-20 membrane spanning domains, 4-5 per subunit
  • Open when ligand binds to extracellular part of channel 
  • (5 M2 helicases are sharply kinked inward halfway through the mebrane forming a constriction)
  • Excitatory neurotransmitters eg acetylcholine and glutamate induce opening of cation channels 
  • Inhibitatory neurotransmitters eg GABA (gamma-aminobutyric acid) and glycine induce opening of anion channels 

Nuclear receptors

  • Target for many hormones
  • Cytoplasmic or nuclear proteins
  • Ligand binding domain and DNA binding domain
  • Modulate gene expression
  • Upregulate or downregulate protein production 

Three families:

  • Steroid receptors (androgen/oestrogen/glucorticoid receptors)
  • Thyroid/retinoid receptors (vitamin D/retinoic acid/thyroid/peroxisome proliferator-activated receptors
  • Orphan receptors

Kinase linked receptors

  • Mediate the actions of a wide variety of protein mediators eg growth factors, cytokines and hormones
  • Large extracellular ligand-binding domain connected via a single membrane spanning helix to an intracellular domain
  • intracellular domain possesses kinase activity 

Main types include:

  • Receptor tyrosine kinases (eg epidermal growth factor, nerve growth factor and insulin receptors)
  • Serine/threonine kinases (eg transforming growth factor)
  • Cytokine receptors (eg colony-stimulating factor)

G-Protein Coupled receptors 

  • Membrane located - inner side of plasma membrane
  • 400 gene sequences for GPCRs
  • eg muscarinic ACh receptors, adrenoreceptors, dopamine
  • Most have extracellular N-terminus, 7 transmembrane domains and an intracellular C-terminus
  • Universally called 7-transmembrane receptors (7TM receptors)
  • Called G-proteins because of their interaction with guanine nucleotides GTP and GDP
  • G-protein system consists of three subunits (alpha, beta and gamma)
  • Trimer in resting state
  • GTP molecule binds to alpha subunit

GPCRs are divided into three groups

  • Family A: largest, comprising mostly of monoamine, neuropeptide and chemokine receptors
  • Family B: includes receptors for some other peptides such as calcitonin and glucagon
  • Family C: smallest: metabotropic glutamate and GABA receptors 

[Read more for some GPCR specifics]

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