Neurobio Exam 1

The Neuron

Fundamental unit of the nervous system, structural diversity, specialized for electrical signaling through action potentials

Axon hillock

Point in space where signal is initiated or not

Dendrites

Receive and integrate signals, perform computation to fire or not to fire an action potential

Axons

Distribution of signal output, 1 to over 100,000 inputs and/or outputs per cell, and where signals get relayed to?

Synapses

Specialized junctions between nerve cells where chemical neurotransmitters are released from pre-synaptic terminal (axon) to post-synaptic receptors (dendrites) on target cells

Membrane Polarity

The inside is slightly negative and the outside is slightly positive

Transient differences are electrical signals being conveyed throughout nervous system

Membrane potential (Vm)

The difference in charge across the membrane, in most neurons -60 to -80 mV

Action Potential

Transient deviations in membrane potential, big ones in the axons

The primary information carrying electrical signal of the nervous system, consist of a rapid change in voltage across cell membrane (neg to pos) which is propagated the length of the cell

Synaptic Potential

Stimulation of neuron, many small ones travel down dendrites to soma where AP is triggered or not

Knee Jerk Neural Circuit

Tendons tapped, connected to quads stretch quad muscles initiating action potential back to the spinal cord, connects via excitatory synapse to excitatory motor neurons and inhibitory to interneurons.

Extensor muscle activation (quadricep) and flexor-inhibiting (hamstring) interneurons

Two critical features of neuronal membranes for ion flow

Non-uniform distribution of ions across the membrane (a concentration gradient) AND Selective Permability

Non-uniform distribution of ions across membrane

Concentration gradients provide the potential energy causing ions to flow

Created by ion transporters (pumps) which use energy (from ATP)

Selective permeability

Certain ions can flow across membrane at any moment in time. By allowing ion flow, converts the concentration gradient into an electrical current (turns potential to kinetic energy)

Since many channels are capable of opening and closing they can regulate ion flow

K+

More concentrated inside, and membrane fairly permeable to it so diffuses out

Outward diffusion creates membrane potential

Equilibrium potential of K+

The point where membrane potential and concentration gradient reach equilibrium

Where Vm is now equal to Ek

Ek = -84 mV

Sodium-Potassium Pump

The Intracellular facing pump binds 3 Na+ and ATP comes and is phosphorylated causing a conformational change to face extracellularly. The pump’s lower affinity for Na+ causes the 3 ions to release outside and higher affinity for K+ causes 2 ions to bind. Then the pump is dephosphorylated back to original conformation

Electrochemical Equilibrium

When concentration gradient driving K+ out is balanced by an equal and opposite electrical gradient pulling K+ back in

Magnitude of equilibrium potential

Is entirely dependent on the magnitude of the concentration gradient

The greater initial concentration gradient, the larger electrical force needed to counterbalance it.

[K+] outside

5 mM

[K+] inside

140 mM

When membrane potential is -84 mV

There is electrochemical equilibrium and no net flow of K+

Vm = Ek

Ek equals

Around -84 mV

If Vm > Ek

K+ flow out

A reduction towards -84 mV, inside more pos

If Vm < Ek

K+ flow in

An oxidation still towards -84 mV, inside more neg

Na+ Cl- Ca2+ more concentrated

Outside the cell and therefore mostly flow in

ENa equals

Around +50 mV

Ecl equals

Around -55 mV

Flow of Na+ in makes Vm

More positive

Flow of Cl- in makes Vm

More negative

Cell at rest

More permeable to K+ and somewhat Cl- not Na+

Shakes out to Vm around -60 to -70 mV 

Between Ek and ECl

Vrest

Membrane potential when cell is not firing an AP or receiving signals

When Vm is at or near Vrest

Cell is hyperpolarized

When Vm is less negative, zero, or positive

Cell is depolarized

AP Phase 1 Depolarization

Depolarizes from rest, slow rise to threshold as Na+ channels open and ions flow in

AP Phase 2 Rising, Overshoot

Fast depolarization as cations rush in, overshoot where inside of cell more positive than outside of cell

AP Phase 3 Falling

At threshold K+ channels open and Na+ channels inactivate, repolarizes

Undershoot

Vm < Vrest

AP Peak Vm (+40 mV)

Is near ENa because Na+ rushing in and depolarizing

Subthreshold

When the stimulus is < -40 mV, signals decays back to baseline

Suprathreshold

When stimulus is > -40mV and Vm rapidly shoots up to around +40 mV (action potential)

Low Na+ Influx

Action potential peak amplitude is much lower but Vrest does not change

Lowered K+ Efflux

Alters Vrest but has very little effect on action potential amplitude

Pk > > PNa

At rest so Vm is hyperpolarized close to Ek

PNa > > PK

During action potential so Vm depolarizes close to ENa

Pna is Voltage dependent

Influx of Na+ is triggered by an initial small depolarization (and then there is a positive feedback loop)

Rising Phase Fast Positive Feedback Loop

Na+ entry causes increased membrane depolarization causes increased Na+ permeability 

Na+ Influx

Fast and transient

K+ efflux

Slower and delayed

Na+ influx and K+ efflux

Similarly are voltage-dependent, both currents activated by depolarization

Differently timed

When stimulus depolarizes membrane above threshold

Pna go up, Na+ go in, Vm go up

After 1 msec above threshold

Pna decreases, Vm go down, Pk go up, K+ go in

During undershoot

Pk stays high therfore Vm closer to Ek at rest

Slower Neg Feedback loop

Depolarized above threshold, opens K+ channels, K+ goes out, hyperpolarizes

Refractory Period

Cells can’t fire action potentials within about 2-4 msec of each other

Absolute refractory period

Pna (Na+ flow) remains inactive for a few msec

Relative refractory period

Na+ channels are no longer inactive, but Pk is too high to reach threshold again

Inactivation is

Time-dependent

Passive Propagation

Signals decay exponentially with distance due to ion leakage (ex: small subthreshold depolarizations like synaptic inputs in dendrites)

In dendrites and axons

<0.5 msec to travel 1mm

Active Propagation

APs in axons do not decay across distance and time because new APs are generated in each point in space

In axons only

~ 2msec to travel 1mm

Active propagation is

Reliable but slow

Passive propagation is

Decaying but fast

Saltatory conduction

Fast, passive conduction between nodes, where action potentials are regenerated at Nodes of Ranvier because that’s where Na+ channels are

Myelin

Increases electrical resistance of the membrane, preventing leakage, allowing more passive propagation

APs can be regenerated less frequently and jump from node to node

Myelin advantages

Faster transmission, more passive

Cheaper, less ion channels and sodium-potassium pump doesnt have to work as hard

Smaller axon diameter unlike invertebrates

Multiple Sclerosis

When myelin is removed from axons

First tingling toes because those are longest axons

Ion channels

Allow ions to flow across the membrane a high rate

10,000 ions per channel per msec

bidirectional, flow down electrochemical gradient

Ion channels are

Selective

Many voltage dependent, some ligand gated

Some inactivate

Patch Clamping

Voltage clamp to record current flow through a small patch of membrane containing ion channels allowing direct study of electrical properties of single ion channels

Developed by Sakmann and Neher in 1970s

Current (I) vs. Time, but small currents from a single channel

4 ways neurobiologists record electrical activity in neurons

Extracellular, Intracellular, Voltage clamp, Patch Clamp

Extracellular recording

Voltage changes outside the cell (not Vm) versus time

Standard Intracellular Recording

Membrane potential (Vm) versus time

Voltage clamp

Current (I) versus Time

Na+ Patch Clamp Recordings

Open channel shows down peaks (because cation entering)

Probability of the channels opening increases when depolarized

Each channel has similar conductivity but open and close independently

When Vm goes up

Pna goes up (Na+ ion flow)

Integral Multiples

Current flow occurs in them of a basic unitary current

Two types of K+ Channels

Leak and Voltage-dependent

Leak K+ Channels

Open at rest, responsible for relatively high Pk of resting membrane and therefore for hyperpolarized Vrest

Voltage-dependent K+ channels

ONLY open when depolarized during AP, responsible for repolarization and undershoot.

MUCH higher Pk than the other one

Types of Voltage-gated channels

Na+, Ca2+, K+, Cl-

Types of ligand-gated ion channels

Nt receptor, Ca2+ activated K+ channel, Cyclic nucleotide gated channel

Voltage Gated Ion channel structure determining function

Ion selectivity, gating, inavtication

VGIC Ion selectivity

Determined by size and charge of the channel pore

Negative let in cations and vice versa

Four binding sites strip hydration sphere

VGIC Gating

Regulated by conformational changes of voltage sensor

VGIC Inactivation

Conformational changes of inactivation domain

A ball and chain or a hinged lid

Why K+ channels open more slowly than Na+

Because the helical linker is stickier than the hinge of VGNaC

How ion channels vulnerable to toxins and genetic mutation

Alteration of voltage sensor, inactivation domain and pore can mess up function in many ways

Paramyotonia Congenita

Nav1.7

Bind to specific parts of the channel to block its functional properties: like blocking binding, making less voltage sensitive, change how/whether channel inactivates, which ions flow through.

Myotonia

Any condition where muscles fail to relax normally after activation

Paramyotonia Congenita

Mutations in inactivation domain of certain Na+ channels found in muscle fibers, channels stay depolarized. 

Associated with congenital epilepsy?

Nav1.7 Mutations lead to

Congenital indifference to pain and the man on fire syndrome

Na+ cannot flow through channels on nociceptors or increased activation

Epilepsy

Mutations affecting inactivation in Na+ channels expressed in parts of the brain

How fast repolarization and how long refractory period lasts affected by

Variation in voltage-dependence, kinetics, and inactivation

K+ channel diversity

Specializes neurons, functional differences with ion flow, some have long-lasting, slow APs with lots of NT release but will be poor at representing rapidly changing inputs. Others short rapid firing APs good for rapidly changing input like in the ear

-Some channels open when depolarized

-Some channels open when hyperpolarized

-Some channels open after a depolarizing stimulus ends

-Some channels inactivate (like Na channels), but many don’t inactivate

-Some are activated by calcium ions

-Some are activated by a combination of calcium ions and depolarization

-Some are activated by pH changes (increased pH)

Types of voltage-dependent Ca2+ channels

Cav1 (L-type), Cav2 (P/N/R type), Cav3 (T-type)

Cav1 (L-type)

Function in contraction, muscle cells: high-voltage threshold, Ca2+ dependent inactivation (negative feedback)

Cav2 (P/N/R type)

Function in secretion (presynaptic, triggers exocytosis): intermediate voltage thresholds and inactivation times

Cav3 (T type)

Help excite neurons, similar to voltage-dependent Na channels (though slower): contribute to repetitive firing, low threshold and fast inactivation

Electrical Synapses

Current flows directly from one neuron to the next through pores called gap junctions that form a connexon

No transmitter, synaptic delay very short, good at synchronizing neurons through direct flow

Chemical Neurotransmission First evidence

Stimulate heart Vagus nerve in a liquid solution connected to another heart in another liquid solution by a tube transferring the chemical transmitters released by first heart’s vagus nerve stimulation. yk? yk.

Chemical Synaptic Transmission

1.Action potential triggers a chemical neurotransmitter to be released from presynaptic terminal.

2.Neurotransmitter diffuses across synaptic cleft and binds to receptor proteins in membrane of postsynaptic cell.

3.Binding of transmitter to receptor triggers opening (or closing) of ion channels, causing

4.Current to flow into (or out of) postsynaptic cell.