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Neurophysiology
Learning Outcomes
- Compare graded potential and action potential. Characteristics, locations, and ion channels responsive for each.
- Membrane proteins and ion distributions when a resting membrane potential is reached.
- Membrane potential calculations. Similar to the practice we did in class. Also know the main difference between the Nernst and GHK equations.
- Temporal and spatial summations.
- Mechanisms to trigger NTs release in the axon terminal.
- EPSP vs IPSP.
- What is all-or-none?
- Three membrane proteins contribute to the resting membrane potential:
- Potassium K+ leak channels (60%, most important because the resting cell membrane is much more permeable to K+ than to Na+ or Ca2+. These are always open like a door that is closed but not completely sealed)
- Na+ leak channels (30%)
- Na+/K+ pump (10%) ļ§ Pumps 3 Na+ out for every 2 K+ pumped in ļ net influx of negative charge
Changes in the Membrane Potential
Cells change ion permeability by opening/closing existing channels in the membrane ļ ion movement takes place ļ membrane potential changes, creating an electrical signal Ion channels
- There are four major types of selective ion channels in the neuron: (1) Na+ channels, (2) K+ channels, (3) Ca2+ channels, and (4) Cl- channels
- There are three types of ion channels:
- Mechanically gated ion channels are found in sensory neurons and open in response to physical forces such as pressure or stretch.
- Chemically gated ion channels in most neurons respond to a variety of ligands, such as extracellular neurotransmitters and neuromodulators or intracellular signal molecules.
- Voltage-gated ion channels respond to changes in the cellās membrane potential. Voltage- gated Na+ and K+ channels play an important role in the initiation and conduction of electrical signals along the axon The speed with which a gated channel opens and closes also differs among different types of channels. Channel opening to allow ion flow is called channel activation. For example, voltage- gated Na+ channels and voltage-gated K+ channels of axons are both activated by cell depolarization. The Na+ channels open very
rapidly, but the K+ channels are slower to open. The result is an initial flow of Na+ across the membrane, followed later by K+ flow.
Open vs Closed vs Inactivated
- Open: ion flow
- Inactivated: no ion flow, cannot be opened
- Closed: no ion flow, can be opened
Voltage gated Na+ channel:
The channel has two gates (activation and inactivation gates) leading to three states, closed, open
and inactive.
- When cell membrane depolarizes, activation gate swings open ļ starts positive feedback
loop (Na+ channels open ļ depolarization ļ more Na+ channels open)
- Inactivation gates stop the feedback loop after 0.5 ms. Na+ influx stops ļ action
potential peaks. This ensures unidirectional signal movement
- As neuron repolarizes, gates reset to respond to the next depolarization.
Voltage-gated K+ channel (called the delayed rectifying K+ channel)
This channel has only two states, closed and open.
Opens with a strong depolarization, the type you would normally get in an action potential.
Closes when the membrane becomes hyperpolarized or repolarized.
Graded vs Action Potentials
Voltage changes across the membrane can be classified into two basic types of electrical signals: graded potentials and action potentials
- Graded potentials: variable-strength signals that travel over short distances and lose strength as they travel through the cell - Action potentials: very brief, large depolarizations that travel for long distances through a neuron without losing strength
- mechanical stimuli (e.g. stretch) or chemical stimuli open ion channels in sensory neurons - an open channel closes, decreasing movement of ions Graded potentials can be excitatory or inhibitory :
- Excitatory = depolarizing
- Inhibitory = hyperpolarizing Stimulus too small (subthreshold) ļ graded potential is not strong enough to depolarize the cell to threshold at the trigger zone at the axon hillock ļ no action potential Stimulus strong enough to cause an action potential (suprathreshold) ļ graded potential depolarizes the cell above threshold at the trigger zone ļ action potential triggered EPSPs and IPSPs
- Excitatory postsynaptic potentials = EPSPs
- Inhibitory postsynaptic potentials = IPSPs
Peak of Action Potential
- As soon as the cell membrane potential becomes positive, the electrical driving force moving
Na+ into the cell disappears. However, the Na+ concentration gradient remains, so Na+
continues to move into the cell. As long as Na+ permeability remains high, the membrane
potential moves toward the Na+ equilibrium potential (ENa) of +60 mV. (Recall that ENa is the
membrane potential at which the movement of Na+ into the cell down its concentration gradient
is exactly opposed by the positive membrane potential
-Eventually, a peak at around +30mV is reached. At this point:
i) Na+ channels move into an inactive state (automatically happens after 1-2ms after first
opening; in inactive state they cannot be reopened)
ii) delayed K+ channels open
Together, these initiate a fall in action potential.
Falling Phase of Action Potential
-After the peak is reached action potential falls, membrane potential falls back towards rest
- therefore the membrane potential now determined mostly by K+ (same as for resting potential)
and membrane starts to repolarize as K+ ions flow out of the cell
- When the falling membrane potential reaches -70 mV, the K+ permeability has not returned to
its resting state ļ Efflux of K+ through both voltage-gated and K+ leak channels continues
- Membrane hyperpolarizes to -90 mV. At -90 mV, voltage-gated K+ channels to close.
Retention of K+ and leak of Na+ into the axon bring the membrane potential back to -70 mV.
Refractory Periods
Absolute Refractory Period
- time required for the Na+ channel gates to reset to their resting positions - 1-2 ms - During this time, another action potential cannot be triggered - Because of the absolute refractory period: - a second action potential cannot occur before the first has finished - action potentials moving from trigger zone to axon terminal cannot overlap and cannot travel backward Relative Refractory Period - Some but not all Na+ channel gates have reset to their original positions; K+ channels are still open - The Na+ channels still open can be reopened by a stronger-than-normal graded potential The refractory period is a key characteristic that distinguishes action potentials from graded potentials. If two stimuli reach the dendrites of a neuron within a short time, the successive graded potentials created by those stimuli can be added to one another. If, however, two suprathreshold graded potentials reach the
action potential trigger zone within the absolute refractory period, the second graded potential has no effect because the Na+ channels are inactivated and cannot open again so soon.
depolarizes from local current flow, its Na+ channels open, allowing Na+ into the cell,
propagating the action potential. The continuous entry of Na+ as Na+ channels open
along the axon means that the strength of the signal does not diminish as the action
potential propagates itself.
4. As each segment of axon reaches the peak of the action potential, its Na+ channels
inactivate. During the action potentialās falling phase, K+ channels are open, allowing K+
to leave the cytoplasm. Finally, the K+ channels close, and the membrane in that segment
of axon returns to its resting potential.
5. Although positive charge from a depolarized segment of membrane may flow backward
toward the trigger zone 5 , depolarization in that direction has no effect on the axon. The
section of axon that has just completed an action potential is in its absolute refractory
period, with its Na+ channels inactivated. For this reason, the action potential cannot
move backward
Saltatory Conduction
Happens in neurons with a long axon ā including ALL motor neurons and many neurons in the
CNS.
- Axon is myelinated; small sections of bare membraneāthe nodes of Ranvierāalternate
with longer segments wrapped in multiple layers of membrane (the myelin sheath)
- Myelin sheath creates a high-resistance insulation preventing ion flow out of the
cytoplasm
- Conduction process is similar to that of an unmyelinated axon, but occurs only at the
nodes of Ranvier. The action potential ājumpsā from node to node = saltatory
conduction
- Multiple sclerosis is the most common and best-known demyelinating disease.
Autoimmune disease which attacks myelin. Conduction fails in neurons ļ muscle
weakness not due to muscles but neurons connecting to them
Neurotransmitters
- Acts as a paracrine signal; target cells located very close to the neuron that secretes the neurotransmitter
- Follow principles of protein-based (lipophobic) ligand action
- Can trigger chemically-gated ion channels (e.g. Na+ channels, Ca2+ channels)
- Can trigger second messenger cascade (e.g. bind to GPCR)
- Can be excitatory or inhibitory, depending on receptor
- Influenced by drugs and diseases
- E.g. Parkinsonās disease: not enough dopamine. E.g. depression: not enough serotonin ļ SSRI.
- After released, will be either recycled or disposed. - Acetylcholine (Ach) - Primarily excitatory
- Used by all motor neurons
- Locations: ļ§ Neuromuscular junctions (synapse between motor neuron and muscle) ļ§ ANS (autonomic nervous system) ļ§ CNS (brain)
- Degraded by AChE, an enzyme which degrades Ach. Not recycled. - Glutamate
- Primarily excitatory (major excitatory neurotransmitter in CNS)
- Discovered by studies of sea slugs, which were small enough to study molecular biology, but big enough to study behavior.
- Linked to memory and learning. ļ§ Memory is not stored in individual neurons, they are stored in synapses. Repetition is key to maintaining and growing synapses. - Gamma-aminobutyric acid (GABA)
- Primarily inhibitory (main inhibitory neurotransmitter in the brain)
- Opens ligand-gated Cl- channels ļ Cl- enters cell ļ§ Inhibitory action: makes neurons less likely to fire. ļ§ Used in tranquilizers, anesthesia ļ§ Involved in alcohol. Triggers gaba release ļ neurons fire less.
- Reuptake into axon terminal and glial cells occurs by GABA transporter - Norepinephrine - Mainly excitatory - Major neurotransmitter of the PNS autonomic sympathetic division - ANS (sympathetic) CNS ļ§ Mood ļ§ Motivation ļ§ Alterness - NE transporter for reuptake
Note: Brain weights about 2% of body weight, consumes 15-20% of blood flow. Needs a lot of ATP, produces a large amount of waste products ļ blood flow through brain must be very efficient.
