Module 7

Current: the flow of charge

• movement of electrons

• movement of other ions

Copper is a good conductor of electricity because it has 1e- in its outermost shell that can be easily displaced.

Silicon is a good insulation as it has 4e- in its outermost shell so it is more stable.

Electrical synapse:

• gap junctions connect cardiac muscle cells, allowing movement of small things

Voltage: electrical driving force, electrical potential difference

• difference between 2 cells

Resistance: is opposite to the passage of current

Ohm’s Law: current = voltage/ resistance

AC (alternating current):

• flow of electrical change periodically reverses direction

• frequency of 60 Hz

• action potentials act like an AC current

  • alternates between a resting potential, a depolarization phase (more positive), a repolarization phase (back to negative), and a hyperpolarization phase (sometimes more negative than resting)

  • alternates between positive and negative voltage

DC (direct current):

• the flow of electric charge (electrons) in same direction

• negative terminal to the positive terminal of a power source

• does not cross 0V

• blood pressure acts like a DC current

  • unidirectional from from the heart to the tissues and back

In an electrical circuit, the flow of electrons is opposite to the flow of positive charge.

Cycle frequency (Hertz)

• unit of frequency of complete cycles per second

• applies to changes in state or cycle in a sound wave, alternating current or cyclic waveforms

• eg. 120 pumping cycles/ 60 seconds = 2Hz

• passes 0V twice per cycle

Fluorescent lighting:

• any strong voltage causes tube to emit light

• light emission dims when voltage = 0

• AC power alternates 60 times per second (at a frequency of 60 Hz), the voltage reaches zero twice within each cycle

• for every cycle (which lasts 1/60th of a second), the fluorescent light dims twice

• therefore, the light dims 120 times per second — twice per cycle at 60 Hz

Ionic current: flow of ions

• ions have physical mass and charge (but electrons are very light)

  • movement down chemical and electrical gradients (same or opposite directions)

Equilibrium potentials:

K+ and Cl- in solution with different concentrations in each cell

• more KCl in cell I than in cell II

1. initially, charge balance; no electrical gradient

2. now, membrane is permeable to K+ only

   • K+ moves down concentration gradient, not net change built up yet

   • K+ moves from cell I to cell II

3. net charge develops

   • cell II is more positive than cell I

   • eventually, driving force of electrical charge gradient = driving force of concentration gradient

   • very little total K+ movement

Membrane potential (mV)

• measures inside relative to outside

• when only K+ is permeable, net movement of K+ from inside to outside; at equilibrium, reading is -58 mV (outside the cell is 0)

  • negative because K+ is moving from inside to outside, inside becomes more negative

• when only Na+ is permeable, net movement of Na+ from outside to inside; at equilibrium, reading is +58 mV

  • positive because the inside has an influx of Na+ making it more positive

Work required to move chemical species = RT ([ion outside]/[ion inside])

Work required to move charged particles across electrical gradient = zFE

• z is the number of charges per particle (i.e. Cl-, z= -1)

At equilibrium, there is no net flux because electrical work cancels out chemical work.

zFE = RTln ([ion outside]/[ion inside])

Nernst equation: at 18 degrees C

E = (0.058 / z ) x (log[ion outside]/log[ion inside])

Frog Muscle cell:

• resting membrane potential = -92 mV

• indicates that something else is permeable

• Na+, K+, Cl- are typically the biggest players

• at rest, PK is 100x greater than PNa

• PCl is very small

Goldman equation:

E (Na+, K+, Cl-) = (RT / z ) x (PK[ion outside] + PNa[ion outside] + PCl[ion inside] / PK[ion inside] + PNa[ion inside] + PCl[ion outside]

• negative ions are flipped

• Cl is very small so you can ignore it

Na+/K+ are the most important players when membrane is at rest. Membrane is most permeable to these ions at rest.

Leak channels, open at rest allow relatively high P (permeability) to K+ at rest.

Negative current electrode is made positive when pierced while submerged in positive bath electrode.

• positive current flows into the cell

Excitable cells:

• hyperpolarization

  • negative current inward

  • Vm becomes more polarized (more negative)

• depolarization

  • positive current inward

  • Vm becomes depolarized (more positive, closer to 0)

Intracellular AP

• all-or-none

• if threshold is not reached, AP will not fire

• once threshold is reached, AP will fire and stimulus intensity is no longer related AP intensity

• threshold voltage: average voltage at which enough voltage-gated Na+ channels open for it to lead a cycle

• singular neuron

Compound AP

• stronger stimulus → more axons fire → larger compound AP

• measure of combined activity

• minimum stimulus intensity = intensity necessary to trigger at least one or a few axons to fire AP

The Hodgkin Cycle: positive feedback cycle

• Na+ channel opens → Na+ enters cell → membrane depolarizes → more Na+ channels open

• inside the cell is negatively charged so it is attracted to sodium

• strong inward electrical gradient

Action potentials are a result of voltage-gated ion channels.

• The voltage-gated Na+ channel is rapidly activated by depolarization and becomes inactivated even if Vm remains depolarized.

• The voltage-gated K+ channel is activated by depolarization but more slowly than the Na+ channel; it is inactivated slowly and not completely if Nm remains depolarized.

Na+/K+ ATPase pump is NOT directly responsible for repolarization after individual action potential.

• As the membrane potential becomes more positive, K⁺ ions flow out of the cell, contributing to the falling phase of the action potential (repolarization).

• Nothing will drag the membrane voltage below the resting potential if the equilibrium potential of K+ can’t

The electrochemical gradient of Na+:

• below 0V, concentration gradient in & electrical gradient in; Na+ influx, both gradients in the same direction

• at 0V, concentration gradient in & no electrical gradien; Na+ influx

• slightly above 0V, concentration gradient in (larger) & electrical gradient outward (smaller); reduced but net influx

• at ENa+, concentration gradient in & electrical gradient out are equal; no net movement, and gradients are equal and opposite.

The electrochemical gradient of K+:

• above 0V, concentration gradient out & electrical gradient out; K+ outflux, both gradients in the same direction

• at 0V, concentration gradient out & no electrical gradient; K+ outflux

• slightly below 0V, concentration gradient out (larger) & electrical gradient in (smaller); reduced but net outflux

• at EK+, concentration gradient out & electrical gradient in are equal; no net movement, and gradients are equal and opposite.

Na+/K+ ATPase helps maintain ion concentrations.

• activated by Na+ in and K+ out

• it takes many APs before the pump activity increases enough to notice

Absolute Refractory Period:

• period during which AP cannot be triggered (no matter the intensity)

• occurs during the peak of an AP

• voltage-gated Na⁺ channels are either open or inactivated

• ensures unidirectional event and prevents the nerve or muscle from being overstimulated

• too many inactivated Na+ channels for successful Hodgkin Cycle

Relative Refractory Period

• period during which excitability is reduced (threshold is high and resulting AP is weaker)

• occurs after the absolute refractory period

• the membrane is partially repolarized, but some Na⁺ channels have returned to a "ready" state

• the cell is hyperpolarized, so it requires a stronger stimulus to activate an AP

• helps control frequency

• only some Na+ channels ready so Hodgkin Cycle is harder to start

The slower the depolarization stimulation, the less synchronized the opening of voltage-gated ion channels is.

• threshold for triggering AP will be higher

Refractory occurs when an inactivation particle rapidly closes voltage-gated Na+ channel. This is when repolarization is established.

AP propagation is unidirectional

1. influx of Na+

2. ions quickly diffuse into cytosol and along cytosol

3. begins to depolarize first section of membrane and approaches threshold until its opened and Na+ comes in

4. previous channels are in absolute refractory period

Length constant:

• distance reached where only 63% of voltage is declined

• measured away from stimulus

• Vm decreases exponentially

• more Na+ channels fired further along the axon increases the length constant

• depends on membrane resistance and longitudinal resistance

To increase the length constant:

1. decrease the magnitude of the denominator (longitudinal resistance)

   • larger axon radius → smaller longitudinal resistance → axons conduct faster

2. increase numerator (membrane resistance)

   • insulate with myelin sheaths (less leak channels)

Larger axons

• invertebrate solution for faster AP conduction

• 5 giant axons in earthworms to initiate the escape response

• squid can grow large for jet propulsion fo escape response

Increase myelination

• oligodendrocyte (CNS only)

• schwann cell (PNS only)

• only axons can be myelinated

• increase membrane resistance (prevent leak) and reduce membrane capacitance (organization) allowing free flow

• threshold is so high where myelinated so APs can only occur at Nodes of Ranvier

Saltatory conduction:

1. AP generated

2. Na+ enters the axon and spreads towards the next node

3. elevation of intracellular Na+ depolarizes the membrane at the next node causing voltage gated Na+ changes to open there

4. APs “jump” or “leap” from node to node

Electrical synapses:

• 2 connexion molecules form gap junctions; 6 connexin molecules form 1 connexion

• not always permanently open

• allow flow of ions, H2O, and small molecules

• fastest type of synapse

• used for “escape behaviour”

• asymmetric electrical synapses exist where opening of gap junctions is elicited by depolarization but sometimes only connexion channels on one of the two membranes responds strongly to depolarization

Graded potentials:

• travel short distances

• conduction with decrement: magnitude of graded potential decreases with increasing distance

  • due to leakage, resistance, properties of membranre

1. injections of small stimulus current into cell A

2. graded (sub-threshold potentials) depolarization occurs

3. + current both leaks out of cell A and moves through electrical synapse

4. results in smaller-magnitude graded depolarization in cell B (not enough to generate AP)

APs:

1. superthreshold stimulating current injected into cell A

2. AP fires in cell A

3. passive leakage of current across electrical synapse results in depolarization of cell B

4. depolarization of cell B beyond threshold elicits AP in cell B

Fast chemical synapse: ligand-gated ion channels

• binding of ligand (neurotransmitter) causes ion channels to open

1. terminal at rest

2. AP arrives, synapse vesicles fuse with terminal membrane producing exocytosis of transmitter (vesicles released at active zone)

3. transmitter binds to post synaptic receptor proteins; ion channels open

• come removed transmitter is degraded while others are recyles into synaptic vesicles

Nicotinic synapse:

• ligand is ACh (acetylcholine)

• nicotine mimic ACh

• 2 binding sites

• ACh binds and results in the depolarization of post-synaptic membrane

• when bound to nicotine, the channel can flicker open and closed because nicotine binds with lower affinity than ACh

1. no ACh bound - channel closed

2. ACh binds - channel opens

   • can flicker open/close

3. channel can close and stay closed with ACh bound

   • “desensitized state”

   • won’t be able to reopen until another ACh binds and old one unbinds

   • ACh is broken down by acetylcholinesterase in cleft

• channel is permeable to both Na+ and K+

  • allows Na+ to flow in and K+ to flow out, but Na+ influx is stronger

Electromotive force (EMF):

• driving force for movement of an ion

  • sum of strength of electrical and chemical gradients

• difference between Vm and the equilibrium potential for an ion

• negative means influx of sodium moving in, Vm is below ENa+

Ionic conductance:

• ionic current for an ion is the magnitude of its driving force multiplied by its permeability

• permeability x EMF

• at rest, permeability for Na+ is low, so ionic current is small

• variation of Ohm’s law:

  • I = V/R

  • resistance is the inverse of permeability (g): R = 1/g

  • I = g(V or EMF)

Reversal potential:

• when ionic current for one ion is equal and opposite to another ion

• -IK+ = INa+

• Erev = gNa(EMF Na) + gK(EMF K)

• since nicotinic channel is equally permeable to Na+ and K+ when open Erev = (1/2)(Ek +ENa)

1. no EMF for Na+, large K+

   • big net + outside

2. I Na < I K

   • net + out but smaller than prior

3. I Na and I K are equal and opposite

   • no net current

4. I Na > I K

   • net + current in

5. I Na » I K

   • big net + inside

The result is a graded depolarization.

GABA fast inhibitory synapse:

• normally ECl = -100mV (similar to EK)

• GABA activates channels permeable to Cl-

  • net Cl- entry

  • hyperpolarization

Slow chemical synapse:

• neurotransmitters that are larger molecules

• not released at active site; indirect action

1. neurotransmitter binds to receptor

2. causes activation of G-protein complex

3. G-protein complex directly or indirectly causes change in conductance through ion channel

   • opens or closes depending on synapse

4. G-protein activated second messenger causes other cell changes

Neurotransmitter recycling:

• deactivated or removed from synapse

• endocytosed

  • in fast synapse: transmitter produced and reformed/repackaged in axon teminus

  • in slow synapse: transmitter produced and reformed/repackaged in soma (intracellular trafficking)

Four functional neural zones:

• signal reception:

  • dendrites and cell body (soma)

  • incoming signal received and converted to change in membrane potential

• signal integration:

  • axon hillock

  • strong signal is converted to an AP

• signal conduction:

  • axon

  • AP travels down axon

• signal transmission:

  • axon terminals

  • release of neurotransmitter/ electrical synapse

Signal integration:

• post-synaptic graded potential decays with distance

  • AP is only generated if potential is reaching axon hillock as superthreshold

• axon threshold has a higher threshold than the rest of the soma

  • which is why it is the integration point

  • densed with voltage-gated ion channels

Excitatory synapse:

• EPSP - excitatory post-synaptic potential

• causes post-synaptic membrane to depolarize

Inhibitory synapse:

• IPSP - inhibitory post-synaptic potential

• causes post-synaptic membrane to hyperpolarize

Spatial summation:

• neurons are typically innervated by many axons

• multiple simultaneous postsynaptic potentials from different locations on the postsynaptic membrane combine to influence the overall membrane potential

Temporal summation:

• same synapse can be fired in succession

• single presynaptic neuron fires repeatedly in quick succession

• post synaptic potential degrades slower than actual current exists

  • postsynaptic current is faster to disappear because of the rapid movement of ions when the channels are open

  • postsynaptic potential, the result of that ion movement, can last longer because it takes time for the membrane potential to return to normal after the current has stopped

Neuronal plasticity:

• modification of neuronal function as a result of experience

• presynaptic changes

  • homosynaptic modulation: activity in terminal itself causes changes in patterns of neurotransmitter release

  • heterosynaptic modulation: changes in presynaptic activity induced by action of another closely associated axon terminal

Neuromuscular junction (NMJ)

• frog NMJ: homosynaptic facilitation

• curare in bath blocks some of the ACh receptors

  • resulting EPSPs are not strong enough to generate AP

  • graded potentials are only measured

• 2 stimulation pulses in quick succession

• magnitude of second is greater than the first

Vm depolarization from APs also cause voltage-gated Ca2+ channels to open in the presynaptic terminal

• Ca2+ influx triggers exocytosis

• extent of exocytosis related to amount of intracellular Ca2+

• after AP, Ca2+ levels don’t fall instantaneously

• second pulse of presynaptic Ca2+ influx adds onto previous pulse raising the concentration even higher

• more robust exocytosis

  • more ACh-receptor activation

Sensory receptors:

• ranges single to complex sense organs

• type of stimulus: chemoreceptors, mechanoreceptors, photoreceptors, electroreceptors, magnetoreceptors, thermoreceptors

  1. receptor protein detects stimulus

  2. opening or closing of ion channel

  3. changes in membrane potential

  4. signal sent to integrating center (CNS)

Location of stimulus:

• telereceptors: detect distance stimuli

  • vision and hearing

• exteroceptors: stimuli outside of the body

  • pressure and temperature

• interoceptors: stimuli inside the body

  • blood pressure and blood oxygen

1. structural/conformation change in transmembrane protein

2. activation of G-protein complex results (direct or second messenger) in modification

3. net ion flux

Taste receptors operate in a simpler way:

• salt: passive movement of Na+ ions into receptor cell, directly causes depolarization

• sour: activation of pH-sensitive K+ channels directly cause hyperpolarization

All stimuli are ultimately converted into APs in a primary afferent neuron/

Sensory receptors and neurons encode stimulus modality, location, intensity, and duration.

APs along various sensory neurons are all the same, what parts of the brain the neurons feed tell us the type of sensation.

Tonic sensory neurons:

• produce APs as long as the stimulus continues

• encodes duration

• receptor adaption- AP frequency decreases if stimulus intensity is maintained at the same level for a long period of time

Phasic sensory neurons:

• produce APs beginning and/or end of a stimulus

• encode a change in stimulus

• when stimulus is received or not received

Limits to encoding:

• amplitude of receptor cell potential related to log intensity of stimulus

  • receptor potential amplitude does not increase linearly with stimulus intensity

• frequency of APs relates to current strength and total amplitude

  • refractoriness of neurons dictates maximum AP frequency

• range fractionation

  • individual sensory neuron respond to given range of stimulus intensity

  • multiple sensory neurons may respond differently over a greater range of stimulus intensities

Vertebrate proprioceptors:

• muscle spindle

  • contract along with other fibers

  • don’t really generate a force, they are for sensing

• participate in negative feedback loop to cause reflexive resistant to muscle (over-) stretching

• reflex arc

  • inhibit antagonistic muscle that might be causing lengthening

  • excite muscle they are part of

• important to have natural brake to prevent run-away muscle activity

Insect mechanoreceptors:

• campaniform sensillum

• spine mechanically coupled to dendrite of bipolar neuron

• bending of the spine in one direction causes a depolarizing current

  • but less in the other direction

• ion channel activation can be directly connected to mechanical movement

  • extracellular fluid high in K+

  • opening allows influx of K+

  • opposite to vertebrates