NEUR3006 – Semester 1
Lecture 1: Neuron excitability
P1.1: Write down the Nernst Equation. Use arrows to identify each term and explain the key variables that
influence resting membrane potential
• All living cells of the body have an electrical potential difference across their peripheral membrane (Vm)
• The resting membrane potential (resting Vm) is the Vm when the neuron is inactive.
+ +
o Outflow of K is balanced by an equal inflow of Na (created by inward chemical and electrical driving
+
forces acting on Na )
Key Regulators Equilibrium potential - EK and ENa Features
(when electrical potential =
chemical force of ions)
+ +
Role of -75mV Chemical driving force for K causes K to diffuse down its
potassium concentration gradient (from inside to outside).
+
Role of sodium +55mV Vm never reaches EK due to slow outward diffusion of K being
+
balanced by slow inward diffusion of Na via leak channels
+ +
Relative Resting Vm = -65mV due to membrane being 20 x more permeable to K than Na (Vm closer to Ek
permeability than ENa)
P1.2: Explain the relationship between the resting membrane potential and the Nernst Potentials for
sodium, potassium and chloride ions
• The Nernst potential for potassium (EK) tells us where potassium would take the Vm if potential is potassium
dependent [applies to all ions]
CHEMICAL AND ELECTRICAL DRIVING FORCE:
• The direction and magnitude of the chemical driving (vector arrow) depends on:
o the concentration difference across the membrane
o temperature.
• Ions cannot cross the lipid bilayer require a protein channel.
+ +
• K leakage channels on the peripheral membrane allow continual slow leakage of K out of the cell enough to
polarize membrane and produce unbalanced negative charge for resting potential
nd
• The Vm constitutes 2 force: the electrical driving force which acts upon all ions
,Goldman Equation
+ + -
The Goldman Equation models the combined contributions of K , Na and Cl ion movements to the resting Vm (Chloride
ions also play a role in determining Vm)
Role of the sodium/potassium pump
+ + + +
• The Na / K -ATPase pump actively transports 3 Na out of the cell and 2 K into cell but has minimal effect on Vm
as it is very slow
+ +
• Inhibiting pump will cause Vm to become less negative hence Na / K -ATPase pump maintains concentration
+ +
gradients of K and Na over the long term
P1.3: Explain the characteristic features of the axonal voltage-gated sodium channel that contribute to
generating the action potential
Neuronal signalling is rapid:
• Synaptic potentials and action potentials occur quickly over a millisecond timescale due to rapid changes in relative
permeability of ions
+ +
• Sudden increases to Na permeability will increase the rate of Na influx, in the same proportion, causing
depolarisation.
+
• Local increase in Na influx produces an excitatory postsynaptic potential (EPSP) or graded potential (not involved
in Hodgkin Cycle) to cause a transient rise in Vm above its resting level
o Amplitude of the increase in Vm depends on how many ligand-gated cation channels open at the synapse.
P1.5: To what does the term ‘synaptic potential’ refer?
• Synaptic potential refers to the difference in voltage between the inside and outside of a postsynaptic neuron
• In motor neurons, depolarising synaptic inputs (EPSPs) trigger APs, which move down a myelinated motor neuron
axons via saltatory propagation (100m/s)
• The neuromuscular junction (NMJ) is a chemical synapse that operates through:
1. Depolarisation of the motor nerve terminal by AP causes the opening of voltage-gated calcium channels
2+
(VGCCs) releasing Ca from ECF into axon terminal
2+
2. Ca binds to sensor proteins on synaptic vesicles to trigger exocytosis of ACh from inside the synaptic
vesicle into the synaptic cleft.
3. ACh binds to and triggers the opening of acetylcholine ligand-gated cation receptors (AChRs) on the
+
postsynaptic membrane to allow influx of Na into postsynaptic membrane
§ Brief opening of AChR channels produces small (quantal) depolarisation called the miniature
endplate potential
§ Each quantal response sum together to produce the large amplitude postsynaptic depolarisation
called the endplate potential (EPP)
4. If EPP reaches threshold, this triggers an action potential and thus, the Hodgkin cycle in the muscle fibre.
,P1.4: Describe the properties of the axonal voltage-gated potassium channel that complement the role of
the sodium channel in creating action potentials
What does the VGSC contribute to the action potential shown Here?
+
• Action potentials are produced by the rapid opening of Voltage-gated Na channels (VGSC) when the graded
potential causes the Vm to exceed the threshold value causing a brief, exponential rise in the membrane
permeability resulting in rapid depolarization of the cell membrane.
+
• This is followed by a slow transient increase in the permeability of K (causing repolarization and subsequent
hyperpolarization)
What 2 gates are there on the VGSC and the properties of each gate type?
Gate Properties Effect Note:
+
Activation gates Open rapidly in response to Increased influx of Na Both the activation and the
depolarisation of the membrane causes neighbouring VGSCs inactivation gates must be
+
to open (this is the Hodgkin open for Na to pass
cycle). through the channel
Inactivation gates When the membrane is depolarised Repolarisation stops
+
for a short time (< 1ms), these gates influx of Na
close
Explain: “hyperpolarisation” + “after hyperpolarisation” + “period of reduced excitability”
+
• Voltage-gated K channels (VGKC) also respond to the depolarisation, but their activation gates are intrinsically
slower to open.
+
• VGKCs open to increase the rate of K efflux causing the Vm to return from +40mV (peak) to EK
• Repolarisation of AP = Inactivation of VGSC and opening of VGKC
o VGKCs are also slow to close their activation gates after membrane repolarization explaining
afterhyperpolarisation or the period of reduced excitability.
Explain “the Hodgkin Cycle”
The Hodgkin cycle represents a positive feedback loop in which an initial membrane depolarization leads to
uncontrolled deflection of the membrane potential to near ENa.
, 2. MOTOR UNITS AND MOTOR NEURON POOLS
1. Skeletal muscle is stimulated to contract by release of ACh into synaptic cleft of neuromuscular junction
+ +
2. ACh binds to nicotinic ACh receptors to create influx of Na and efflux of K
3. Sufficient depolarization generates an AP along the sarcolemma
4. AP transmitted to Transverse-tubules which stimulate dihydropyridine receptors linked directly to ryanodine
receptors on SR
2+
5. Stimulation of ryanodine receptors release Ca stored in SR into the sarcoplasm of the muscle fibre to allow
contraction through the cross-bridging cycle
2+
6. An active transporter pump protein works continuously to pump Ca from the cytoplasm back into the SR to
end contraction
*Contraction continues as long as sufficient calcium, ATP and stimiulus is present (tetanus)
2+
1. Destabilisation Ca binds to troponin, tropomyosin fibres changes
conformation to reveal actin binding site
* troponin stabilises tropomyosin in a cross bridge
2+
blocking position when Ca not bound
2. Binding: Myosin cross-bridges (thick filaments) can bind
with actin molecules (thin filaments)
3. Power Stroke Cross bridge bends, pulling thin myofilament
inward
4. Detachment Cross bridge detached at end of power stroke and
returns to original conformation
5. Binding Cross bridge binds to more distal actin molecules
and cycle repeats
How much force is generated?
2+
• Amount of force generated depends on cytoplasmic [Ca ]i , which depends upon the action potential frequency.
o Thus, higher frequencies cause an increase tetanic contraction force up to about 150Hz.
• Force produced by a skeletal muscle is dependent on:
1. # of fibres contracting in a muscle
2. Amount of force developed by each contracting fibre
Lecture 1: Neuron excitability
P1.1: Write down the Nernst Equation. Use arrows to identify each term and explain the key variables that
influence resting membrane potential
• All living cells of the body have an electrical potential difference across their peripheral membrane (Vm)
• The resting membrane potential (resting Vm) is the Vm when the neuron is inactive.
+ +
o Outflow of K is balanced by an equal inflow of Na (created by inward chemical and electrical driving
+
forces acting on Na )
Key Regulators Equilibrium potential - EK and ENa Features
(when electrical potential =
chemical force of ions)
+ +
Role of -75mV Chemical driving force for K causes K to diffuse down its
potassium concentration gradient (from inside to outside).
+
Role of sodium +55mV Vm never reaches EK due to slow outward diffusion of K being
+
balanced by slow inward diffusion of Na via leak channels
+ +
Relative Resting Vm = -65mV due to membrane being 20 x more permeable to K than Na (Vm closer to Ek
permeability than ENa)
P1.2: Explain the relationship between the resting membrane potential and the Nernst Potentials for
sodium, potassium and chloride ions
• The Nernst potential for potassium (EK) tells us where potassium would take the Vm if potential is potassium
dependent [applies to all ions]
CHEMICAL AND ELECTRICAL DRIVING FORCE:
• The direction and magnitude of the chemical driving (vector arrow) depends on:
o the concentration difference across the membrane
o temperature.
• Ions cannot cross the lipid bilayer require a protein channel.
+ +
• K leakage channels on the peripheral membrane allow continual slow leakage of K out of the cell enough to
polarize membrane and produce unbalanced negative charge for resting potential
nd
• The Vm constitutes 2 force: the electrical driving force which acts upon all ions
,Goldman Equation
+ + -
The Goldman Equation models the combined contributions of K , Na and Cl ion movements to the resting Vm (Chloride
ions also play a role in determining Vm)
Role of the sodium/potassium pump
+ + + +
• The Na / K -ATPase pump actively transports 3 Na out of the cell and 2 K into cell but has minimal effect on Vm
as it is very slow
+ +
• Inhibiting pump will cause Vm to become less negative hence Na / K -ATPase pump maintains concentration
+ +
gradients of K and Na over the long term
P1.3: Explain the characteristic features of the axonal voltage-gated sodium channel that contribute to
generating the action potential
Neuronal signalling is rapid:
• Synaptic potentials and action potentials occur quickly over a millisecond timescale due to rapid changes in relative
permeability of ions
+ +
• Sudden increases to Na permeability will increase the rate of Na influx, in the same proportion, causing
depolarisation.
+
• Local increase in Na influx produces an excitatory postsynaptic potential (EPSP) or graded potential (not involved
in Hodgkin Cycle) to cause a transient rise in Vm above its resting level
o Amplitude of the increase in Vm depends on how many ligand-gated cation channels open at the synapse.
P1.5: To what does the term ‘synaptic potential’ refer?
• Synaptic potential refers to the difference in voltage between the inside and outside of a postsynaptic neuron
• In motor neurons, depolarising synaptic inputs (EPSPs) trigger APs, which move down a myelinated motor neuron
axons via saltatory propagation (100m/s)
• The neuromuscular junction (NMJ) is a chemical synapse that operates through:
1. Depolarisation of the motor nerve terminal by AP causes the opening of voltage-gated calcium channels
2+
(VGCCs) releasing Ca from ECF into axon terminal
2+
2. Ca binds to sensor proteins on synaptic vesicles to trigger exocytosis of ACh from inside the synaptic
vesicle into the synaptic cleft.
3. ACh binds to and triggers the opening of acetylcholine ligand-gated cation receptors (AChRs) on the
+
postsynaptic membrane to allow influx of Na into postsynaptic membrane
§ Brief opening of AChR channels produces small (quantal) depolarisation called the miniature
endplate potential
§ Each quantal response sum together to produce the large amplitude postsynaptic depolarisation
called the endplate potential (EPP)
4. If EPP reaches threshold, this triggers an action potential and thus, the Hodgkin cycle in the muscle fibre.
,P1.4: Describe the properties of the axonal voltage-gated potassium channel that complement the role of
the sodium channel in creating action potentials
What does the VGSC contribute to the action potential shown Here?
+
• Action potentials are produced by the rapid opening of Voltage-gated Na channels (VGSC) when the graded
potential causes the Vm to exceed the threshold value causing a brief, exponential rise in the membrane
permeability resulting in rapid depolarization of the cell membrane.
+
• This is followed by a slow transient increase in the permeability of K (causing repolarization and subsequent
hyperpolarization)
What 2 gates are there on the VGSC and the properties of each gate type?
Gate Properties Effect Note:
+
Activation gates Open rapidly in response to Increased influx of Na Both the activation and the
depolarisation of the membrane causes neighbouring VGSCs inactivation gates must be
+
to open (this is the Hodgkin open for Na to pass
cycle). through the channel
Inactivation gates When the membrane is depolarised Repolarisation stops
+
for a short time (< 1ms), these gates influx of Na
close
Explain: “hyperpolarisation” + “after hyperpolarisation” + “period of reduced excitability”
+
• Voltage-gated K channels (VGKC) also respond to the depolarisation, but their activation gates are intrinsically
slower to open.
+
• VGKCs open to increase the rate of K efflux causing the Vm to return from +40mV (peak) to EK
• Repolarisation of AP = Inactivation of VGSC and opening of VGKC
o VGKCs are also slow to close their activation gates after membrane repolarization explaining
afterhyperpolarisation or the period of reduced excitability.
Explain “the Hodgkin Cycle”
The Hodgkin cycle represents a positive feedback loop in which an initial membrane depolarization leads to
uncontrolled deflection of the membrane potential to near ENa.
, 2. MOTOR UNITS AND MOTOR NEURON POOLS
1. Skeletal muscle is stimulated to contract by release of ACh into synaptic cleft of neuromuscular junction
+ +
2. ACh binds to nicotinic ACh receptors to create influx of Na and efflux of K
3. Sufficient depolarization generates an AP along the sarcolemma
4. AP transmitted to Transverse-tubules which stimulate dihydropyridine receptors linked directly to ryanodine
receptors on SR
2+
5. Stimulation of ryanodine receptors release Ca stored in SR into the sarcoplasm of the muscle fibre to allow
contraction through the cross-bridging cycle
2+
6. An active transporter pump protein works continuously to pump Ca from the cytoplasm back into the SR to
end contraction
*Contraction continues as long as sufficient calcium, ATP and stimiulus is present (tetanus)
2+
1. Destabilisation Ca binds to troponin, tropomyosin fibres changes
conformation to reveal actin binding site
* troponin stabilises tropomyosin in a cross bridge
2+
blocking position when Ca not bound
2. Binding: Myosin cross-bridges (thick filaments) can bind
with actin molecules (thin filaments)
3. Power Stroke Cross bridge bends, pulling thin myofilament
inward
4. Detachment Cross bridge detached at end of power stroke and
returns to original conformation
5. Binding Cross bridge binds to more distal actin molecules
and cycle repeats
How much force is generated?
2+
• Amount of force generated depends on cytoplasmic [Ca ]i , which depends upon the action potential frequency.
o Thus, higher frequencies cause an increase tetanic contraction force up to about 150Hz.
• Force produced by a skeletal muscle is dependent on:
1. # of fibres contracting in a muscle
2. Amount of force developed by each contracting fibre
