The Doogie mouse

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The Doogie mouse
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Dales principle

• Dales principlea neuron releases the same
  neurotransmitter at all its synaptic terminals.
• Neurons appear to be metabolically setup for
  particular NTs
• Postsynaptic responses to the same NT can vary
  widely

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How to identify a NT

• NT must be present in the presynaptic terminal
  with its precursors and synthetic enzymes.
• NT must be released upon presynaptic stimulation.
• Application of NT should produce same effects as
  stimulation.
• A mechanism for removal must exist. (peptides?)
• Effects of drugs on neurotransmission must be
  consistent with effects of NT when applied within
  an experimental protocol.

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NT criteria

• NT criteria does not account for gases that may
  function as NT.
• The criteria are difficult to establish
  experimentally at particular synapses.
• The list of possible and probable NT is greater
  than those that have been demonstrated to be NT.

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Modes of Action

• Most synapses in CNS use AA NTs.
• Glutamate produces EPSPs.
• GABA produces IPSPs
• Biogenic amines are in few neurons that project
  widely with broadly distributed endings.
• Peptides are in substantial minorities of neurons
  and are often cotransmitters with AA NTs and
  biogenic amines.

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Multiple receptors

• NTs often have more than one type of receptor.
• Fast vs slow effects
• IPSPs and EPSPs
• Two ACh receptors
• Nicotinic receptor is ionotropic and produces a
  fast signal, found at NMJ
• Muscarinic receptor is metabotropic and is found
  on cardiac muscle.

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Neurotransmitters2 kinds

• Small molecule NTs
• AAs are the most abundant NT
• Neuroactive peptides

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Termination of NT actions

• Release, diffusion and binding of NT happens in a
  few milliseconds.
• Temporal and spatial effects are regulated by
  enzymatic destruction or by uptake.
• Breakdown of ACh occurs within 5ms of release.
• NT is taken up by presynaptic cells, glial cells
  and other neurons.
• Recycling NT includes uptake into vesicles, which
  is an active process that occurs against a
  gradient.

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Peptide and small molecule synthesis

• Small molecule NTs are synthesized in axon
  terminals.
• Peptides are synthesized in the cell body.
• Made up of 3-55 AAs.
• Synthesized as propeptides and transported to
  terminal where they are cleaved into smaller
  pieces and/or active forms.
• Peptides are degraded by peptidases and are not
  taken up.

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Conservation of NT systems

• The same NTs are found in a wide range of
  organisms.
• The NTs are often functioning in different roles.
• ACh is major excitatory NT at NMJ in vertebrates
  but glutamate plays same role in arthropods.
• ACh plays a sensory role in arthropods but
  glutamate plays a similar role in vertebrates

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(No Transcript)
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Figure 12.16 The molecular structure and
function of a ligand-gated channel (Part 1)
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Figure 12.16 The molecular structure and
function of a ligand-gated channel (Part 2)
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Ionotropic receptors

• Produce direct effects by opening ligand gated
  ion channels.
• ACh nicotinic receptors
• Produce an all-or-none response.
• Opening the channel depends on concentration of
  ACh.
• The net ionic current contributes to synaptic
  potential.
• The currents through all channels can summate.
  This is the synaptic current.

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Figure 12.17 Patch-clamp recordings of
acetylcholine receptorchannel currents
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Evolution and ligand gated channels

• Ligand gated channels evolved from a common
  ancestor called the ligand-gated channel
  superfamily.
• Receptors for glutamate are superficially similar
  but have multiple subunits of greater weight and
  probably evolved separately.

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Metabotropic receptors

• Metabotropic receptors
• Alter permeability to ions to indirectly change
  Vm
• Induce metabolic changes that dont gate ion
  channels.

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Figure 12.18 Metabotropic receptors cyclic AMP
as a second messenger
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Figure 12.19 G proteincoupled neurotransmitter
receptors activate G proteins (Part 1)
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Figure 12.19 G proteincoupled neurotransmitter
receptors activate G proteins (Part 2)
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Figure 12.20 G proteins can activate ion
channels, without a second messenger
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Neurotransmitter effects

• G proteins can directly act on channels
• Channels can be gated by a number of mechanisms
• Voltage
• Ligand binding
• G proteins

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cGMP and calmodulin

• G proteins can activate guanylyl cyclase to
  produce cGMP
• cGMP activates cGMP-dependent protein kinase
  which phosphorylates proteins.
• Ca2 ions bind to cytoplasmic protein calmodulin.
• Activation of calmodulin can activate
  calcium/calmodulin-dependent protein kinase.

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Figure 12.21 Diacylglycerol and inositol
trisphosphate are other second messengers
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Metabotropic actions

• G-protein coupled receptors represent most of the
  metabotropic receptors.
• All have 7 membrane spanning regions and are
  evolutionarily related.
• G-proteins have 3 subunits, a is the activated
  unit, b and g have regulatory roles.
• G-proteins activate an intracellular effector.
• Second messengers include cAMP, DAG, IP3 and Ca2
  ions.
• Second messengers activate protein kinases, which
  phosphorylate ion channels and other proteins,
  changing their activity.
• Metabotropic receptors also produce slow synaptic
  potentials and can decrease permeability of
  membrane to ions.