Ion Channels in APs

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Psy 111 Basic concepts in Biopsychology Lecture
5 Synaptic Transmission
Website http//mentor.lscf.ucsb.edu/course/summer
/psyc111/
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Objectives

• Describe the parts of the neuron involved in
  chemical synaptic transmission and the
  specializations in these parts.
• Describe the general processes that occur
  presynaptically.
• Generation and storage of neurotransmitter.
• Conversion of action potential into
  neurotransmitter release.
• Role of Ca in exocytosis.
• Identify the different types of post-synaptic
  responses to neurotransmission, including
  electrical synapses.
• Describe factors determining the strength of
  postsynaptic potentials, including the role of
  driving force (particularly for Na and K
  channels) and inhibitory postsynaptic potentials.
• Discuss integration of postsynaptic potentials
  including connection between site of synapse and
  its strength.
• Describe metabotropic receptors with emphasis on
  G-protein systems.
• Identify components of the cAMP and IP3/DAG
  messenger systems.
• Discuss factors which lead to termination of
  neurotransmission.

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Ion Channels in APs
Rest open K channels (not voltage-gated)
-65 mV
Rise open Na channels (voltage-gated)
-65 mV
Fall open K channels (voltage-gated)
-65 mV
-80 mV
Rest open K channels (not voltage-gated)
-65 mV
Q What would happen to the action potential
without the voltage-gated K channels?
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Conduction by Na Channels
Generator Potential Need 10 mV input to reach
threshold
But where does this come from?
But where does this end up?
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Compartmentalization
Dendrites input Body protein
production Initial Segment integration Axon
conduction Terminal output
Output of a neuron is based on chemical
transmission which turns the electrical signal
(frequency of APs) into chemical signal (amount
of transmitter released).
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Electrical synapses

• Gap Junction - Adjacent cells have
  inter-connected channel allowing transfer of
  ionic currents.
• Electrical coupling of cells.
• Junctions can be gated.

-fast, reliable -coupling of neurons (rare)
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Chemical Synapses
Axon terminal responds to incoming action
potential by releasing neurotransmitter i.e.
convert electrical into chemical signal.
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Presynaptic Activity NT synthesis, storage,
Exocytosis
Proteins for synthesis, storage and release of
neurotransmitters are generated in soma and
transported to axon terminal.
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NT Release (pre-)Exocytosis

• Where the vesicles are
• Vesicles containing neurotransmitters are
  transported to axon terminal via the cytoskeleton
  (fast axonal transport).
• Cytoskeleton links to docking proteins
• Vesicles are transferred to docking proteins and
  are ready for release.
• Reserve vesicles are continually generated and
  move to docking proteins during neurotransmitter
  release

for many neurotransmitters synthetic proteins
are contained in vesicles and neurotransmitter is
synthesized from precursors in the terminal.
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NT Release Docking Proteins

• Docking proteins hold vesicle in place and ready
  for release.
• Complex involves several distinct proteins
• v-, t- snares vesicle docking proteins
• Synaptotagmin Ca sensing SNARES

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Vesicle Docking Exocytosis
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Action Potential-Exocytosis Coupling


Na
Na

• Along the axon, Na carries the ionic current
  (depolarization).
• In the axon terminal, Ca carries the ionic
  current.
• Voltage-gated Ca channels.
• Ca acts as signal for vesicle release.

Na
Na

Ca

Ca
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Action Potential-Exocytosis Coupling
Note Ca acts as a signal it is not membrane
depolarization that directly triggers vesicle
release.
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Summary of neurotransmitter release.
Axon terminal responds to incoming action
potential by releasing neurotransmitter. i.e.
convert electrical into chemical signal.
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Compartmentalization
Dendrites input Body protein
production Initial Segment integration Axon
conduction Terminal output

• Dendrites have specialized proteins for chemical
  detection receptors.

• Input into a neuron is based on chemical
  transmission which is turned into an electrical
  signal (i.e. generator potential).

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Postsynaptic Activity
Neurotransmitter
Metabotropic Receptors Transmitter-activated
enzymes e.g. G-proteins.
Ionotropic receptors Transmitter-Gated Ion
Channels
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Excitatory Post-Synatpic Potential (EPSP)
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Inhibitory Postsynaptic Potential (IPSP)
Channels that make the membrane more permeable to
Cl- (or K) oppose generation of AP.
ECl- -65 mV (ie resting membrane potential),
thus Cl- channels only create IPSP when membrane
is depolarized
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Commonalities between transmitter-gating channel
proteins

• All ionotropic receptors have 5 subunits with
  each subunit comprised of four transmembrane
  domains.
• Different receptors will have different
  interactions with neurotransmitters based on
  subunit compositions.

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Recording Post-synaptic Potential

• Miniature postsynaptic potentials
• due to spontaneous release of neurotransmitter
• always same size
• equivalent to single vesicle fusion events
• EPSPs or IPSPs are integer multiples of miniPSPs

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Postsynaptic Potential Size-size of response
following detection of neurotransmitter

• Ipsp N . Po . G . Vdiff
• Ipsp current of EPSP or IPSP (i.e. size)
• N number of channels
• Po probability of opening
• G single channel conductance
• Vdiff (i.e. driving force) Eion - Vm
• -any factor influencing these variables will
  influence the magnitude of the postsynaptic
  potential e.g. different subunits results in
  different conductance.

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Transmitter-Gated Ion Channels
Nicotinc Acetylcholine receptor (nAChR) -5
polypeptide subunits -4 membrane spans per
subunit -only a subunit binds ACh -selective for
Na and K -typically produces EPSPs Why?
So will this lead to EPSP or IPSP????
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Current flow through a nAChR

• Iion g . (Eion Vm)
• At rest (Vm -65 mV)
• ENa Vm 130 mV
• EK Vm -15 mV
• The higher driving force on Na (at rest)
  produces far greater inward Na current than the
  outward K current.
• Thus, nAChR activation leads to depolarization at
  rest Vm.

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Integration of Post-synaptic Signals

• Neurons have 100s-1000s of inputs.
• Inputs are a mixture of ionotropic receptors that
  produce excitatory and inhibitory PSPs (as well
  as metabotropic receptors-later).
• Integration is the NET result of all inputs.

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Integration of EPSPs
Spatial summation from different
neurons. Temporal summation from the same neuron.
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Integration of EPSP with IPSPs
EPSPs and IPSPs summate spatially.
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Site of Synapse and Input Strength

• Axon terminals that are on the soma tend to have
  larger impact on postsynaptic cells because input
  is closer to axon hillock (i.e. closer to
  anatomical site of electrical integration thus,
  less signal degradation).

Axosomatic
Axodendritic
Why does input site matter???
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Signal Degradation

• Magnitude of the signal declines as you move away
  from point of depolarization.
• i.e. like an axon, dendrites are leaky
• Dendrites typically can not regenerate
  depolarization.

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Inhibitory Shunting
Excitatory Synapse receptor coupled ion channel
for Na or Ca
Inhibitory Synapse receptor coupled ion channel
for Cl- or K
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Excitable Dendrites
Dendrites with voltage-gated channels can
maintain depolarization magnitude (i.e. prevent
signal degradation or amplifies signal).
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Postsynaptic Activity
Neurotransmitter
Metabotropic Receptors Transmitter-activated
enzymes e.g. coupled to G-proteins.
Ionotropic receptors Transmitter-Gated Ion
Channels
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Structure of Receptors.

• Metabotropic receptors are comprised of single
  subunit
• Cytoplasmic portion of receptor couples to
  intracellular enzymes.

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Ionotropic vs. Metabotropic Receptors

• Direct coupling fast neurotransmission
• Indirect coupling slow neurotransmission
  tends to have more complex effects on
  postsynaptic cell i.e. modulates

These systems can cause many other changes in
cell
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G-Protein Systems
G-protein-coupled receptor -1 polypeptide -7
membrane spans -binds to G protein -binds
neurotransmiter
G-Protein -3 polypeptides/subunits -binds
G-protein-coupled receptor -binds guanosine
triphosphate (GTP) -have enzymatic activity
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G-Proteins Effector Proteins
Inactivated Effector -No influence on other
proteins

• Activated Effector
• Influence other proteins

Converts neurotransmitter to intracellular
chemical information (i.e. activation of effector
enzymes/proteins).
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Phosphorylation of Proteins
Inactive
Active
Phosphorylation controls protein activity.
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Covalent modulation chemical bonds formed e.g.
adding phosphate Allosteric modulation
changing shape (like chemical-gated channel)
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G-Proteins Second Messengers

• G-Protein activates Primary Effector
• Primary Effector generates a second messenger
• Second Messenger activates second (downstream)
  Effectors

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cAMP system

• cAMP serves as an intracellular (second)
  message for many effector proteins
  cAMP-dependent protein kinases eg protein
  kinase A.
• G-Proteins can turn system on or off ie Gs
  versus Gi
• Note same transmitter can act on Gs or Gi
  therefore effect depends on proteins expressed in
  post-synaptic cell.

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Effectors can modulate gene expression
Downstream Effectors are Transcription
Factors -produces very long-term effects on neuron
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Amplification in 2nd Messenger Pathways
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G-Proteins the shortcut pathway
Activated G-Protein modulates ion
channel -indirect neurotransmitter gating of ion
channel -effects are via phosphorylation of
channel ie long-term gating
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IP3 DAG System
-Both IP3 and DAG serve as an intracellular
messages for many effector proteins divergence
in system -G-Proteins can turn system on or
off -all G-proteins are referred to as Go
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Crosstalk in 2nd Messenger Pathways
Divergence
Convergence
Crosstalk Convergence Divergence
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Effects of slow neurotransmission
Can change concentration gradients e.g.
particularly H or Cl-.
Modulates responsiveness to incoming
neurochemical signals.
Can change resting properties of neurons e.g.
gate K or Na channels to change resting
membrane potential.
Has long-term enduring effects on cell changes
amounts of proteins can also produce chromatin
remodeling
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Termination of Neurotransmission
Reduce NT Release
Remove released NT
Neurotransmission is terminated by shutting off
release and removal of message
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Shutting down release Autoreceptors

• Neurons can have receptors to detect the
  neurotransmitters that they release
  autoreceptors.
• Activation of autoreceptors lead to inhibition of
  exocytosis (i.e. are inhibitory).

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Removing Neurotransmitters
-2 major mechanisms to end neurotransmission 1-reu
ptake transporters in the terminals (or on the
dendrites) take the neurotransmitter back inside
the neuron to be re-packaged or
degraded 2-enzymatic degradation enzymes found
in the synaptic cleft break down the
neurotransmitter after it is released (3-diffusio
n neurotransmitters simply move out of the
synaptic cleft)
Transporter Protein
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Parts of a neuron and their roles in neural
communication
1. Dendrites receive chemical information from
other neurons or sensory information through
receptors
dendrites
Axon