introduction to cardiac electrophysiology - phcol.szote.u...
TRANSCRIPT
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Introduction to cardiac
electrophysiology
2.
Dr. Tóth András
2018
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Topics
• Ion channels
• Local and action potentials
• Intra- and extracellular propagation of
the stimulus
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4 Ion channels
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4.1 Basic features
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Ion channel
Protein (or protein komplex) located within the plasma
membrane, acting as a pore and facilitating selective
transport of ions. Following its activation an ion channel
does generate transmembrane electric current. This current
may flow either „inward” or „outward” direction.
Failure or abnormal function of an ion channel complex
(most typically as a consequence of genetic disorders) may
lead to severe malfunction at the organ level. Indeed, ion
channel related disorders – “channelopathies” – are being
identified as the background pathomechanisms of an
increasing number of diverse human diseases.
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Basic features of ion channels 1.
Motto: For normal cell function precisely controlled and fully synchronized
transport of a wide variety of positive and negative ions is essential.
Ion channels are present within the plasma membrane of all cell types and intracellular
organelles. Inside an ion channel there is a narrow tunnel that allows only ions of certain
size and/or charge to pass through (selective permeability). A given ion channel may either
be “gated” (regulated) or “nongated” (non-regulated).
Compared to „other types of ion transport proteins” ion channels have two important,
distinctive features:
(1) The rate of ion transport through a channel is very high (often > 106 ion/s).
(2) The direction of the passage of ions through the tunnel is determined by
their electrochemical gradient (a function of the concentration gradient and
membrane potential). For the "downhill" ion transport no metabolic energy
(ATP, co-transport or active transport) is needed.
Since they are able to regulate influx or outflux of ions, ion channels are often
direct or many times indirect (!!!) targets for a wide variety of drugs.
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Basic features of ion channels 2.
Motto: Some ion channels are fully regulated (i.e. „gated” channels), others are
pracically nonregulated (i.e. „nongated” – or „leakage” – channels).
„Gated” ion channel – the opening (and sometimes closing) of these channels is
triggered by the income of a specific stimulus. This specific stimulus may be:
(1) change of membran potential (voltage) (voltage gated ion channels)
(2) binding of a specific ligand or signalling molecule (ligand gated channels)
(neurotransmitter, hormon, local hormon) to the channel protein
(3) mechanical stimulus (deformation, pressure, stretch);
(4) light energy (photon);
Since a ”gated” ion channel is regulated – it only opens following the income of the
adequate trigger signal. The closing, however, may be both controlled or spontaneous.
„Nongated” (or leakage) ion channel – is always open (or leaking) and facilitates the
passage of one or more ion types in direction of their electrochemical gradient.
A ”nongated” channel is nonregulated, as well, (i.e. further to the electrochemical
potential the transport flux is solely a function of the temperature.
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1 – channel domains
(typically four per channel)
2 – outer vestibule
3 – „selectivity filter”
4 – diameter of the „selectivity
filter”
5 – site of phosphorylation
6 – plasma membrane
Principal structure of an ion channel
A typical channel pore is only one-two atoms wide at the
narrowest point and is selective for its specific ion (Na+, H+, K+).
Nonetheless, several ion channels are less selective and let pass
more that one type of ion, usually with the same type of charge:
cations (positive charges) or anions (negative charges).
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Ion channels are involved in a huge variety of cellular functions, many of which has
critical importance: e.g. chemical signaling, transcellular transport, pH regulation,
regulation of cell volume, etc.
Their significance is especially prominent in the nervous system (e.g. generation
and propagation of the nerve impulses, signal propagation through the synapses
via transmitter-activated ion channels, etc. (Most animal venoms and toxins –
produced by spiders, snakes, scorpions, sea snails, bees, etc. – are acting by
modulating ion channel conductance and/or kinetics.)
In addition, ion channels are key components of a wide variety of physiological
mechanisms: e.g. excitation-contraction coupling in cardiac, skeletal and smooth
muscles, epithelial transport of nutrients and ions, activation of the immun system,
insulin release from the beta-cells of the pancreas, etc.
Not surprisingly, many ion channels are among the most favoured targets
of the pharmaceutical research.
Biological roles
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There are over 300 types of functional ion channels in a living cell.
Their classification can be accomplished in several different ways: by the
nature of the „gating” mechanism, the species of ion passing through the
pore, or the structure and/or localization of the channel proteins.
A further heterogeneity arises in the cases when channels with different
constitutive subunits give rise to a single, specific current.
Absence or mutation of one or more of the contributing types of channel or
regulatory subunits may result in loss of function, and potentially underlie
multiple diseases.
Diversity
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Q:
What is the principal difference between
membrane receptor and ion channel?
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Q:
Are there membrane receptors, which also
serve as ion channels?
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4.2 Experimental techniques
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Bert Sakmann – Nobel laureate – developer of the “patch clamp” technique
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Principles of the “patch clamp” technique
Needed:
Electrode + pipette
Special pipette solution
Gigaseal (R > 1GOhm)
Voltage command
Current measurement
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Steps of “patch clamp” recording
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“Patch clamp” configurations
Common investigations:
Single channel current
Current of a channel type or a
group of channels
Special pipette solution –
modification of the IC milieau
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Automated “patch clamp” measurement
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4.3 Principles of regulation
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Simple, “dual-state” ion channel – background channels
spontaneously oscillate between open and closed states
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State diagram of a komplex “multistate” ion channel
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4.4 Biophysical properties
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Determination of “single channel” current
1. A single channels is in either open or closed
state.
2. The open state of a channel is short lived
compared to the time course of the
macroscopic current.
3. The length & latency of the open state is highly
variable, it may happen that the channel
does not open, at all.
4. The probability function of channel opening
correlates with the shape of the
macroscopic current curve.
5. A channel may open several times during a
single cycle if there is no inactivation.
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Integrated (macroscopic) current of two groups of voltage dependent
channels following a voltage command: 1) Na+; 2) delayed K+
The Na+ channel spontaneously inactivates, the K+ channel not
Sum of 300 recordings
„macroscopic
Na+ current
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Determination of the mean open time
Modulation of the channel can be followed in change of the
mean open time
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Current-voltage relationship characteristic for the „inward” and
„outward” rectifying channels
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Current-voltage functions of two groups of ion channels
(Na+ & K+) and their combination
The K+ current shows linear relationship – no voltage-inactivation
The Na+ current is nonlinear because of the voltage inactivation
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Current-voltage relationship of two types of ion channels -
determined in isolated atrial cardiomyocytes
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Principles of activation/inactivation kinetics
Working structural model of slowly inactivating Kv4 type
K+ channels
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4.5 Classification of ion channels
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Voltage-gated ion channels
Their opening (and often closing) is driven
by changes in membrane potential, i.e
the equilibrium state of their spontaneous
oscillation (probability of the open/closed
states) is voltage dependent.
Classification by gating mechanism 1
Functions
They have a crucial role in excitable tissues
(neurons, muscles, glands) by ensuring
excitability and stimulus-propagation.
Depending on circumstances voltage-gated
ion channels allow rapid and synchronized
depolarization in response to voltage stimuli,
but can also contribute to repolarization or
hiperpolarization.
Major subfamilies
- Voltage-gated Na+ channels (Nav)
- Voltage-gated K+ channels (Kv)
- Voltage-gated Ca2+ channels (Cav)
- Voltage-gated H+ channels (Hv)
- Hyperpolarization-activated channels
- Transient receptor potential (TRP)
channels
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Ligand-gated ion channels
Also known as ionotropic receptors - open in
response to specific ligand molecules binding
to a channel protein: e.g. „neurotransmitter-
gated”, „G-protein-dependent”, „modulated”
(kovalent modification – phosphorilation, etc.)
channels. Binding of the ligand causes a
conformation change and subsequent ion flux
across the channel.
These channels are typically involved in initialization of impulses (i.e. early
phase of depolarization of excitable cells – nerves, muscles, glands).
Depending on circumstances they may initiate depolarization, repolarization
or hyperpolarization, as well.
Examples: cation-permeable “nicotinic” acetylcholine receptor, ATP-gated „P2X”
receptors, ionotropic glutamate-gated receptors, anion-permeable GABA receptor.
Sometimes 2-nd messenger-activated channels are also mentioned here, though
ligand and 2-nd messenger are different categories.
Classification by gating mechanism 2
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Classification by gating mechanism 3
„Modulated” channels may also be voltage-
gated, however, covalent modification (e.g.
phosphorylation) also effectively modulates
the probability of the open/closed states.
Probability of the open and closed states of
„G-protein gated” channels is modulated via
binding of a G-protein, activated by activation
of a receptor (e.g. muscarinic Ach receptor)
Other gating mechanisms
Include activation/inactivation from the inside of
the membrane by e.g. second messengers.
Certain ions may also be considered as second
messengers causing direct activation of the
channel (e.g.: inward rectifying K+ channels,
Ca2+-activated K+ channels, two-pore-domain K+
channels
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Classification by gating mechanism 4
Mechanosensitive ion channels (1)
Opening of these channels is triggered by
mechanical stimulus (stretch, shear,
pressure, displacement, vibration)
Light-gated channels (2)
These channels (e.g. channelrhodopsin) are
directly opened by the action of light.
Temperature gated channels
Some TRP receptors (TRPV1, TRPM8) are
opened either by hot (e.g. the capsaicine
receptor) or cold temperatures.
Cyclic nucleotide-gated channels
Two families: 1) the cyclic nucleotide-gated
(CNG) channels (cAMP and cGMP binding),
and 2) the hyperpolarization-activated, cyclic
nucleotide-gated (HCN) channels.
1
2
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Sodium channels
Voltage-gated Na+ channels (Nav)
Epithelial Na+ channels (ENaC)
Potassium channels
Voltage-gated K+ channels (Kv)
Ca2+-activated K+ channels (BKCa, SK, etc.)
Inward-rectifier K+ channels (Kir)
„Two-pore-domain” K+ channels („leak” channels)
Calcium channels
Voltage-gated Ca2+ channels (CaV)
Classification by transported ion type 1
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Proton channels
Voltage-gated H+ channels (Hv), with strong pH dependence
and tiny conductance
Cloride channels
Poorly-understood superfamily of anion channels with at least
13 members. (pl. ClC, CLIC, Bestrophin, CFTR). Nonselective
for small anions. Since cloride is the most abundant transported
anion, they are called cloride channels.
Non-selective cation channels
These channels are permeable to several cations (mainly Na+,
K+ and Ca2+). A number of TRP (transient receptor potential)
channels are also classified into this group.
Classification by transported ion type 2
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Based on less common features, e.g number of transmembrane pores or
transient behaviour of response.
Two pore channels
Small (2 members) cation-selective ion channel family, containing two
KV-style 6-TM domains, probably forming a dimer in the membrane.
Tranzient receptor potential (TRP) channels
This family, containing at least 28 members has extremely diverse
activation properties. Some are probably constitutively open, others
show voltage, [Ca2+], pH, redox state, osmolarity or stretch dependence.
Their selectivity is also greatly variable, some are Ca2+-selective, others
are less selective cation channels.
6 subfamilies: canonical (TRPC), vanilloid (TRPV), melastatin (TRPM), polycystin (TRPP),
mucolipin (TRPML), and ankyrin transmembrane protein 1 (TRPA) .
Further ways of classifications
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Example: superfamilies of K+ channels
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Q:
How is that possible, that Na+ ions may pass an
ion channel, but K+ ions not?
How is that possible, that K+ ions may pass an
ion channel, but Na+ ions not?
Ion Atomic radius (Angstöm) Energy of hydration (kcal/mol )
Na+ 0.95 -105
K+ 1.33 -85
Help
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4.6 Structure
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Representative examples of ion channel “superfamilies”
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S4 helices are the “voltage-sensors” of voltage-gated channels –
amino acid homology is extensive
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2D model for the voltage dependent Na+ channel
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2D model for the voltage dependent Ca2+ channel
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• a) Conventional „gating” model:
The voltage sensor (S4 segment) moves
across the plasma membrane
• b) Novel „paddle” model:
The voltage sensor S4 and S3 segments
compose a „hairpin” outside of the
channel. Activation of the channels is
induced by the rotation of these paddles.
• c) The „transporter” model:
This new model is based on the
assumption that the charges present on
the voltage sensor (S4) do not move
accross the membrane, insteed they
rotate around their longitudinal axes,
shifting the „gating” charges from
extacellular to intracellular position.
Suggested models of activation mechanism of voltage
dependent ion channels
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Contains at least 9 members. Is largely responsible for creation and propagation of
action potentials.
The pore-forming α subunits are very large (up to 4,000 amino acids) and consist
of four homologous repeat domains (I-IV) comprising 6-TM segments (S1-S6)
each. This α subunits also coassemble with auxiliary β subunits, each spanning
the membrane once.
Voltage gated sodium channels (Nav)
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The Cav family contains 10 members. They are known to play a crucial role in
excitation-contraction coupling in the muscles, as well, as their fast neuronal
excitation with transmitter release.
The structure of the α1 subunits have a resemblance to α subunits of the Na+
channels. They are also known to coassemble with other (α2δ, β, γ) subunits .
Voltage-gated Ca2+ channels (Cav)
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This family contains almost 40 members, which are further divided into 12
subfamilies. These channels are known mainly for their role in repolarizing the
cell membrane following action potentials.
The α subunits (homologous to the sodium channels) have 6-TM segments, and
also assemble as tetramers to produce a functioning channel.
Voltage gated potassium channels (Kv)
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Functional model of a voltage-gated K+ channel
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"Birth of an Idea",
2007
1.50 m x 0.90 m x 0.90 m
Steel, glass, wood
Sculpture by Julian Voss-
Andreae based on potassium
channel
Photo by Dan Kvitka
Sculpture commissioned and
owned by Roderick MacKinnon
Please use only with link to
www.JulianVossAndreae.com
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4.7 Structure-function relation
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Model of the function of the S4 helix as „voltage sensor”
A total of 6 charges should relocate in the membrane to open the channel
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Top view of the Na+ channel, showing how the central ion channel
is proposed to be lined by one of the helices from each domain
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„A few” cardiac ion channels
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Cardiac action potentials and major ion currents involved
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Q:
Which are the most important properties
of the ion channels?
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A:
Integral membrane protein
Aqueous pore through the membrane
Selective permeability to one or several small ions
Single channel conductance to ion flow
Rectification - current passes more easily in one than in
other direction
Gating - oscillation between conducting and nonconducting
states
Regulation - gating is influenced by voltage, or binding a
ligand, or covalent modification
Pharmacological modulation !!!
Sites of action of clinically important drogs!!!
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5 Local & action potentials
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5.1 Local response
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Q:
What is the difference between electrochemical
and membrane potentials?
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Local (subthreshold) response
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Q:
Which are the most important features
of the local response?
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Temporal summation
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Spatial summation
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Q:
Special forms of local response?
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5.2 Action potential
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Responses in the membrane potential to increasing pulses of
depolarizing current
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Action potentials from three vertebrate cell types
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Q:
What are the major differences between
local response and action potential?
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5.3 Action potentials in the heart
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Ion concentrations in mammalian heart
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“Fast and slow response” in the heart
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Regional variability in the morphology of the action potential in
cardiac cells
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Q:
What is the main reason for the very different
kinetic properties of the action potentials
recorded in different cell types?
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“Explanation” of the kinetic differences in cardiac AP-s
„Fast”
sodium
„Funny”
„Delayed
rectifier”
Calcium
„Tranzient
outward”
„Background”
Sodium
„Inward
rectifier”
Ion currents
!
I
0
0
„L”
„T+L”
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Q:
How could you change the shape of the
action potential?
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The effect of tetrodotoxin on the fast response
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Q:
What is the effect of tetrodotoxin on
fast response in cardiomyocytes?
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6 Propagation of the stimulus
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6.1 Basic principles of propagation
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Q:
Why is it “feasible” to maintain a large resting
potential in our body cells, if it „costs” us a
large amount of energy (ATP)?
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Potential changes recorded (measured) by an extracellular
electrode located at different distances from the current electrode
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Maximum change in recorded (measured) membrane potential
plott-ed versus distance from the point of current passage
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Potencial changes calculated for a model RC-circuit
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Electric model of the axon membrane
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Time constant determined in a membrane
CRR im
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Model of the decremental propagation (voltage divider -
resistance ratio)
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Length constant determined in the axon membrane
i
m
R
R
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Model of conduction of the local (subthreshold) response
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Electric model for the propagation of potential changes
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Q:
What is the explanation for the well known
fact, that postsynaptic action potentials are
always generated at the axon hillock?
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Model of conduction of the AP in nonmyelinated fibers
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“Saltatory” conduction of the action potential in myelinated fibers
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Conduction velocity of the action potential determined in
unmyelinated and myelinated fibers
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Q:
Which factors determine the conduction velocity of
the action potential in myelinated fibers?
And in unmyelinated fibers?
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Q:
Why is conduction velocity significantly higher in
myelinated then in unmyelinated fibers?
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6.2 AP propagation in heart
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Q:
How would you explain the common statement that
cardiac muscle is “functional syncytium”?
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Structure of the electric synapse (gap junction)
MW 1500Ca2+
pH
Em
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Q:
Where are electric synapses (gap junctions)
located in the mammalian body?
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Q:
Which are the major functional differences
between electric & chemical synapses?
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Electric model of the cardiac cells
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Computer simulation of impulse propagation at the microscopic
level
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Q:
What is the prime factor determining the direction
of impulse propagation in the three dimensional
cardiac muscle?
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Q:
Why is the transmission of stimulus through
the AV node dramatically slower than its
propagation in other regions of the heart?
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Q:
Are there „fast” & „slow” velocities of action
potential propagation in the heart?
What may be the reason?
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The significance of the gap junction system in
physiological stimulus propagation in the heart
Bonus 4 U !!!
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Subcellular stimulus propagation
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Differences in delays of intra- and intercellular activation –
single cell wide network
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Differences in delays of intra- and intercellular activation –
multi-cell wide network
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Impulse propagation (isochron lines) in case of physiological gap
junction coupling (homogenious AP-population)
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Impulse propagation (isochron lines) in severe uncoupling of the
gap junctions (heterogenous AP-population)
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In severe gap junction uncoupling propagation velocity may
decrease TWO orders of magnitude (!!!)
(from 36.7 cm/s to 0.31 cm/s)
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In case of normal gap junction coupling isochron lines are
relatively regularly placed, AP-population is homogenous
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In case of critical gap junction uncoupling action potentials form
clusters with significant delays
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Distribution of the cells forming the different clusters in case of
critical uncoupling – turn back behaviour of the stimulus easily
leading to „reentry” can be observed
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THE END