Action potentials - Axon Initial Segment and the Nodes of Ranvier PDF

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Action Potentials – The “resting” membrane potential NEURO 30002

Dr Garron Dodd [email protected] [email protected]

Department of Physiology School of Biomedical Sciences

Department of Physiology

Learning objectives 1. Understand to molecular mechanisms underlying the resting membrane potential and the action potential. 2. Understand how key molecular changes in the neuronal membrane generate the different phases an action potential. 3. Define where action potentials are initiated and why this occurs. 4. Understand how the axon is specialized to transmit action potentials.

Department of Physiology

This lecture in context

NOTE: The term “potential” refers to the separation of electrical charge across the membrane.

9V

Basic Anatomy of a Neuron

1 Resting Potential

2 Graded Potential

3

1. Resting Potential: The membrane potential when a neurons is at rest. 2. Graded Potential: The graded potential is based on the stimulus received by the neuron 3. Action Potential: We may or may not have an action potential (AP). AP may lead to synaptic activity on the next neuron.

The Movement of Ions Diffusion: there is a net movement of ions from regions of high concentration to regions of low concentration; this movement is called diffusion.

1)

2)

3)

The Movement of Ions Electricity: Opposite charges attract and like charges repel . Consequently, there will be a net movement of Na+ toward the negative terminal (the cathode) and of Cl- toward the positive terminal (the anode).

9V

• The movement of electrical charge is called electrical current (I, amps). Two important factors determine how much current will flow: 1. Electrical potential (V. Volts). 2. Electrical conductance (g).

This relationship, known as Ohm’s law (I = g x V).

The Movement of Ions

Overview: 1. We have electrically charged ions in solution on both sides of the neuronal membrane. 2. Ions can cross the membrane only by way of protein channels. 3. The protein channels can be highly selective for specific ions. 4. The movement of any ion through its channel depends on the concentration gradient and the difference in electrical potential across the membrane.

Resting Membrane Potential (The Membrane at Rest)

K+ =Potassium and A- = impermeable anion

Establishing equilibrium in a selectively permeable membrane Equilibrium is established such that there is no net movement of ions across the membrane, leaving a charge difference between the two sides.

The Distribution of Ions Across the Membrane • K+ is more concentrated on the inside and Na+ are more concentrated on the outside. HOW?

K+

K+Na Na+ Ca Cl+

-

Inside

Outside Na+ Na+

K+ K+

Na+ K+

Na+

Na+

K+

K+

Na+

K+

-ve Protein

Na+

Na+ K+

K+

Na+

K+

-ve Protein

Na+ K+

K+ -ve Protein

Na+

Na+ K+ Na+

There’s no potential (no separation in charges)

Na+

Na+

K+ K+

K+

K+

-ve Protein

K+

K+

K+

-ve Protein

K+

+

-

K+

• There’s a concentration gradient between the K+ on the inside and the outside.

K+ -ve Protein

K+

K+

• There’s also an electrical gradient. The new positive K+ on the outside of the cell will repel each other and want to go back to the cell (-ve). • There’s movement of K+ inside and outside

https://phet.colorado.edu/sims/html/neuron/latest/neuron_en.html

The “Resting” Membrane Potential Uses Energy

N.B. Notice that the pump pushes these ions across the membrane against their concentration gradients

The “Resting” Membrane Potential 1. There’s a separation of ions on the inside and the outside of the cell. 30mV 2. There are different electrochemical gradients establishing a difference in the charge. This generates a resting membrane potential. 0mV

3. The generation of the resting potential requires energy (accounts for ~70% of the brain ATP use). 4. The resting potential is an essential physiological state in order to induce an action potential.

-65mV

Action Potentials – The In’s and Out’s of the Action Potential NEURO 30002

Dr Garron Dodd [email protected] [email protected]

Department of Physiology School of Biomedical Sciences

3

30mV

0mV

Na+ Na+

Na+

Na+

Leak Channels

2 -65mV

1 4

Voltage gated N+ channels are closed at -65mV

Voltage Gated Channels

3

30mV

0mV

Na+

-55mV -65mV

Leak Channels Voltage Gated Channels Na+

Na+

Na+

2 1 4

•

Voltage gated N+ channels are open at around -55mV.

•

If enough channels are opened then there will be a significant influx of Na+ (aka influx of Na+ current) into the cell.

•

If the “activation threshold” of the cell is met then the membrane will become depolarised and the voltage will rise (rising phase and depolarisation).

•

Action potentials are “all or nothing”.

3

30mV

0mV

2 -65mV

Leak Channels Voltage Gated Channels Na+

Na+

Na+

1 4

•

Voltage gated N+ channels are open for around 1ms and then become inactive and close.

•

This will stop the influx of Na + into the cell and the peak of the action potential is reached.

•

The channel will not become active again until the cell has reached back to -65mV.

•

Only one action potential can occur at once.

•

At 30mV K+ channels are open allowing of an efflux of K+ out of the cell (repolarisation).

•

This will repolarise the neuron and bring it back down to resting membrane potential.

•

Eventually there will be a slight overshoot of voltage which will be equilibrated by the Na+ and K + leak channels

3

30mV

0mV

K+

K+

2 1 -65mV

K+

4

Na+ Current K+ Current

Net transmembrane Current

K+

Leak Channels

Voltage Gated Channels Na+

Na+

Na+

Zhou (2017) Front. Pharmacol

The In’s and Out’s of the Action Potential Absolute Refractory Period

30mV

0mV

-55mV

-65mV

Relative Refractory Period

Action Potentials – The Propagation of the Action Potential NEURO 30002

Dr Garron Dodd [email protected] [email protected]

Department of Physiology School of Biomedical Sciences

Propagation of the Action Potential

The Myelin Sheath and Node of Ranvier

Unmyelinated Neuron

Myelinated Neuron

Myelin Sheath

Myelin Sheath

Where are Action Potentials Generated? • Action potentials measured in the soma (black) and in the axon (red). • Sodium spikes usually occur in the axon before those in the soma. • The axon initial segment (AIS) is the initiation zone

Axon Soma

Debanne D et al. Physiol Rev 2011;91:555-602

Where are Action Potentials Generated?

Where are Action Potentials Generated?

• ɴ4-Spectrin and Ankyrin-G are protein that are essential to the organisation of the axonal cytoskeleton. • ɴIV spectrin links ankyrinG (AnkG) which clusters voltage gated channels sodium and potassium channels to the AIS and the Nodes of Ranvier. • Mutations in the genes encoding ankyrin-G or result in severe neurodevelopmental disorders including congenital hypotonia, severe intellectual disability, and motor axonal and auditory neuropathy (Wang et al,. 2018 AJHG) .

Where are Action Potentials Generated?

Immunofluorescence showing colocalization of Nav1.6 and Kv1.2 channels in axon and not the soma (SO) Lorinca (2008) J Neuroscience

Contribution of Nav Channel Isoforms to Action Potentials Nav1.8

Nav1.6

Nav1.1, Nav1.7 1.2 & 1.3

Nav1.6 Nav1.3

Kv

Threshold

Nav1.9

Nav1.9 – Amplification of subthreshold stimuli, ultraslow kinetics. Nav1.1. 1.2, 1.3 – Contributes to amplification of subthreshold stimuli, Low activation threshold, fast kinetics. Nav1.7 – Contributes to rising phase and amplifies subthreshold stimuli, Low activation threshold, fast kinetics. Nav1.6 – Contributes to rising phase, rapid activation and fast inactivation, moderate activation threshold. Nav1.8 – Main contributor to rising phase, high activation threshold, slow kinetics.

Nav1.1

Fast -spiking PV+ interneuron

Hippocampus/corte x

Purkinje cell

Cerebellum

Interneuron

Olfactory bulb

Ganglion cell

Retina Spinal cord

Nav1.2

Immature myelinated axons Retina Pyramidal neuron

Neocortex

Ganglion cell

Retina

Pyramidal neuron

Neocortex

Pyramidal neuron

Hippocampus

Kv1.1

Pyramidal neuron

Neocortex

Kv1.2

Pyramidal neuron

Neocortex

Kv2.2

Medial nucleus trapezoid

Brain stem

Kv7.2/7.3

CA1 and CA3 pyramidal cells

hippocampus

Nav1.6

Graded Action Potentials

1 Resting Potential

2 Graded Potential

3

Graded Action Potentials

Analog

Digital

What You Need To Know 1. Na+, K+ leak channels (passive) and Na+/K+ pump (active) maintain the resting membrane potential at -65mV. 2. Voltage gated channels have specialised properties that facilitate the depolarisation and repolarisation of a neuron. 3. Dendrites integrate information, the soma membrane generates graded potentials. If the summation of graded potentials exceeds the neuronal threshold an action potential will be generated at the axon initial segment. 4. Action potentials travel down the axon due to the high expression of voltage gated channels within the axon. 5. The axons of some neurons are encased with a myelin sheath. 6. Voltage gated channels are expressed highly within the AIS and the nodes of Ranvier. With high levels of NaV within the nodal and Kv within the paranondal and juxtaparanodal aspects of the nodes of Ranvier. 7. Action potentials are generated in the AIS and are progenerated over large distances in a short space of time via the node of Ranvier 8. Distinct NaV isoforms contribute differentially to the generation of the action potential. The expression of Nav isoforms is different between different neuronal subtypes and is plastic....