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156 Cards in this Set

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Describe the basic structural components of a typical plasma membrane of a cell and how the plasma membrane acts as a semipermeable barrier.
Basic components of a typical plasma membrane:
1.Lipid bilayer matrix
2.Intrinsic proteins
(can be extracellular or intracellular, cannot be removed without destroying the membrane)
3. Extrinsic proteins
(only extracellular, can be removed without disrupting membrane integrity)
4. Glycolipids
5. Glycoproteins
6. Cholestrol
_
The plasma membrane acts as a semipermeable barrier in that the lipid bilayer is not miscible with either the extracellular fluid or the intracellular fluid. Therefore, it constitutes a barrier against movement of water molecules and water-soluble substances between the extracellular and intracellular fluid compartments. However, a few substances can undergo simple diffusion to cross. Additionally, the penetrating proteins can function as transport proteins (both channel, which allow for free movement of water as well as selected ions or molecules, and carrier, which bind with molecules or ions that are to be transported). Both the channel proteins and the carrier proteins are usually highly selective for the types of molecules or ions that are allowed to cross the membrane.
State the three general functions for a typical membrane.
1. Serve as reactive surface (receptors, cell markers, signaling cascade components)
2. Serve to compartmentalize the cell:
a. separates the cell from the outside environment
b. an important component of organelles and vesicles
3. Serve to control entry and exit of molecules. Transport is accomplished through channels and transport proteins.
Using Fick's law, describe the factors that affect the diffusion of a molecule across a membrane.
. Fick's law:
Ji = (Di*A*(C1-C2))/X

FICK'S LAW FOR THE PLASMA MEMBRANE:
Ji = Px (Xo- Xi)

where
Ji= the flux of a particular ion
Di = diffusion coefficient of a particular ion
A = the area over which the diffusion takes place
(C1-C2) = the concentration gradient
(Xo-Xi) = the concentrations of molecule "x" inside and outside of the cell.
X= The distance over which the diffusion will take place (ie. the thickness of the memrbane)
Px = permeability coefficient (composed of lipid/water partition coefficient aka beta, diffusion coefficient, membrane thickness, area considered)


Fick's law applies to passive diffusion through an ion channel or lipid bilayer and states that such diffusion is driven by the concentration of different molecules between membranes and results in the "flux" of an ion or molecule.
Define partition co-efficient and describe its significance.
Partition co-efficient aka Lipid/Water Partition coefficient aka Beta

= The ratio of a molecule's solubility in oil to its solubility in water, where a higher number is more lipophilic (0 = soluble in H20; 1=soluble in lipid, more flux)
State and define four different types of carrier mediated movement of molecules across a membrane.
Carrier mediated transport: primary or secondary active transport or facilitated diffusion (passive transport through a pore or channel);

1. Facilitated diffusion
- Does not use ATP and allows ions to flow down their concentration gradient.
-uniport

2. Exchange diffusion
-secondary active transport
-antiport

3. Co-transport
-secondary active transport
-symport

4.Metabolic pump
-primary active transport
State three differences between carrier mediated transport and passive diffusion.
Carrier mediated transport v. passive diffusion:

Passive diffusion:
Fick's law describes simple diffusion which lineraly relates flux with concentration.

Carrier mediated:
1.Transport is dependent on the presence of a protein in the membrane

2. The amount of that protein in the membrane can affect the flux, resulting in Flux function with a nonlinear dependence of ion concentration. As these proteins have a high but limited number, the ion transport asymptotically reaches a maximum as ion concentration goes up, resulting in the curve on the right. *Although a Jmax (maximum flux) exists with carrier mediated and facilitated diffusion, at lower concentrations of ion it is more sensitive to changes in ion concentration than in simple diffusion through a cell membrane.

3. It is not safe to assume that one can use Fick's law to determine the flux through a pore or channel because of protein-ion interaction; instead Michaelis-Mentin kinetics, Km, or half maximal concentration and Jmax maximal flux, must be used to describe that binding that allows transport. In physiological conditions carriers are NEVER SATURATED.
Define co-transport
co-transport:
a form of secondary active transport
Describe how the Na/K pump relocates Na and K against their respective concentration gradients.

What kind of transport is this an example of?
What kind of transporter is this an example of?
The Na+/K+ ATPase pump requires the energy of ATP to pump 3 Na+ out of the cell into the extracellular space (aka interstitial space, aka milieu interior) and 2 K+ into the cell from the extracellular space, both against their gradients. This creates a high Na+ concentration outside and a high K+ concentration inside. Also, since three cations were pumped in, this creates a charge difference (pump is electrogenic, creates a positive charge outside the cell and a negative charge inside the cell).

EXAMPLE OF PRIMARY ACTIVE TRANSPORT
EXAMPLE OF P CLASS ATPase!
Describe the electrogenic nature of the Na/K pump.
The Na+/K+ ATPase pump requires the energy of ATP to pump 3 Na+ out of the cell into the extracellular space (aka interstitial space, aka milieu interior) and 2 K+ into the cell from the extracellular space, both against their gradients. This creates a high Na+ concentration outside and a high K+ concentration inside. Also, since three cations were pumped in, this creates a charge difference. The pump is ELECTROGENIC, creates a positive charge outside the cell and a negative charge inside the cell.

It generates a "-1" charge as 3 Na+ leave the cell and 2 K+ enter.
Name at least four common properties of ion channels.
Components of a typical ion channel:
1. Gate (ex. if it is voltage-sensitive or by a ligand)
2. Ion selectivity Filter
3. Typically they are glycoproteins.
4. Have anchor proteins to keep them stabilized to the lipid bilayer.
5. Voltage sensors or ligand binding site.
Active transport
Active transport:
when a cell membrane moves molecules or ions against a concentration gradient

uses energy (either directly or indirectly in the form of ATP, thus making the transporter an ATPase) to transport ions against their concentration gradient
Antiport
antiport:
uses the energy of transporting one ion down its chemical gradient in order to transport another ion up its gradient in the opposite direction
SECONDARY ACTIVE
Symport
symport:
transports two ions in the same direction, one of them down its gradient, releasing energy to transport the other ion up its gradient
SECONDARY ACTIVE
Define the term "gated channel" and describe the types found in a typical cell
Gated channels (Gated pore) are a type of ion channel in which the channel conduit is gated by a door. Gated channels are responsible for all potentials on the membrane besides the resting membrane potential (the non-gated channel does that). Examples of other potentials that are created by channel/gated pores are action potentials and synaptic potentials.

Gated channels open in response to sound, light, mechanical stretch, voltage, or chemicals. Channels also increase flux for the ion.

Three examples of gated channels:
1. Voltage gated sodium channels:
This channel opens in response to a voltage change in the membrane. It is a multimeric protein and forms an ion channel that selects for sodium. Only sodium can pass through a sodium channel.

2. Gap junction channel: Formed when two hemichannels from adjacent cells simultaneously open and ions pass between the adjacent cells

3. Ligand-gated channel: Binding of ligand (for example acetylcholine) to its receptor causes the channel to open and allow sodium and potassium to move through the channel

4. Mechanical gated: stretch in the membrane can physically open the channel

5. Temperature gated: open at certain temperatures

6. Water channels: aquaporins
Describe the basic structural components of various types of ion channels
Ion channels are multiple-pass transmembrane domain-containing chains of amino acids. The primary amino acid sequence determines the channel structure, and different subunits (amino acid chains) of channels fulfill different roles. On a hydorpathy plot, hydrophobic amino acids make up transmembrane domains and hydrophillic amino acids make up cytosolic or extracellular domains. Ion channels have sequences that alternate between hydrophobic and hydropphillic on the hydropathy plot, indicating that the sequence spans the membrane multiple times. In the example is shown a voltage gated channel. The 6 transmembrane helices found in each subunit have been characterized through hydropathy plots. The N terminal is inside the membrane and transmembrane segments go otu and in until the end. The fifth transmembrane segment, called the B loop, is referred to as the pore domain.

Important:
-each subunit has 6 transmembrane helices
-the 5th domain, known as the P loop (or pore domain) is the site for loose binding of ions
-Changing amino acids in the P loop will alter channel function

1. Tetramers:
Voltage gated Na+, Ca++, and K+ channels
*remember that each subunit consists of 6 domains of transmembrane helices and that the fifth domain, known as the P loop (or pore domain), is the site for loose binding of ions. **CHANGING AMINO ACIDS IN THE P LOOP WILL ALTER CHANNEL FUNCITON

2. Pentamers - nicotine Ach receptor channel (a ligand gated channel in synapses)

3. Hexamers -- connexon - a 6 unit structure that makes up half of an entire gap junction channel. A connexon in a cell's membrane aligns with an adjacent cell's connexon hexamer to propagate electrical potential. Gap junction allows for cell to cell communication.
Ligand gated channel
Ligand-gated channel: Binding of ligand (for example acetylcholine) to its receptor causes the channel to open and allow sodium and potassium to move through the channel.
Gap junction channel
Gap junction channel: Formed when two hemichannels from adjacent cells simultaneously open and ions pass between the adjacent cells
Voltage gated sodium channel
1. Voltage gated sodium channels:
This channel opens in response to a voltage change in the membrane. It is a multimeric protein and forms an ion channel that selects for sodium. Only sodium can pass through a sodium channel.
The cell membrane phospholipids bilayer are made of variable amounts of
-phosphatidyl serine
-phosphatidylcholine
-phosphatidylethanolamine
-cholestrol
What does it mean when you say that the membrane is a reactive surface?
It's a reactive surface because of the different types of protein structures (glycolipids and proteoglycans and glycoproteins for instance which can participate in cell surface recognition and cell surface antigenicity), that are either embedded in it (intrinsic proteins) or attached to it (extrinsic proteins). There are also receptors, cell markers and signaling cascade components.
The intrinsic and extrinsic proteins associated with the cell membrane can move about relative to each other (translational motion), however they may be held in place by:
scaffolding proteins or cytoskeleton containing proteins such as:
-actin
-spectrin
-ankyrin
-dystrophin
Diffusion
as it relates to molecules: the net transport of molecules from an area of high concentration of those molecules to an area of low concentration

aka PASSIVE TRANSPORT
Flux
1. define
2. how can you determine it?
The movement of ions from an area of high concentration to low concentration, measured in an amount of particles per time

Flux is determined by Fick's law:
Ji = (Di*A*(C1-C2))/X

FICK'S LAW FOR THE PLASMA MEMBRANE:
Ji = Px (C1-C2)

where
Ji= the flux of a particular ion
Di = diffusion coefficient of a particular ion
A = the cross sectional area over which the diffusion takes place
(C1-C2) = the concentration gradient
X= The distance over which the diffusion will take place (ie. the thickness of the memrbane)
Px = permeability coefficient (composed of lipid/water partition coefficient aka beta, diffusion coefficient, membrane thickness, area considered)
Flux is driven by?
A concentration gradient (all the other parameters are fixed for a given ion and apparatus - -a pore in a cell, for example)

Since flux is only driven by the concentration gradient, increasing the concentration gradient directly (linearly) affects flux.
Permeability coefficient (Px)
Made up of four components:
1. Lipid/water partition coefficient (beta)
-->The ratio of a molecule's solubility in oil to its solubility in water, where a higher number is more lipophilic (0 = soluble in H20; 1=soluble in lipid, more flux)

2. Diffusion coefficient (Dx)
--> Increasing Dx will increase Jx (flux)

3. Membrane thickness (X)
-->Assumed constant for most membranes (not considering myelin)

4. Area considered
--> typically 1square/micron
FICK'S LAW FOR THE PLASMA MEMBRANE:
Ji = Px (Xo- Xi)

where
Ji= the flux of a particular ion
Di = diffusion coefficient of a particular ion
(Xo-Xi) = the concentrations of molecule "x" inside and outside of the cell.
Px = permeability coefficient (composed of lipid/water partition coefficient aka beta, diffusion coefficient, membrane thickness, area considered)


WHAT HAPPENS WHEN Xo EXCEEDS Xi?
When Xo exceeds Xi, and there is a positive permeability coefficient, net flux of "x" will be INTO the cell. What is REALLY happening is "x" fluxes in both directions, and the inward flux is more than the outward flux. Solutes are in constant motion.
H2O diffuses in and out of a red blood cell each second that is = to
100x the volume of the cell itself
Jmax
Maximum flux

Km = [X] = 1/2Jmax
(just like michaelis-menten kinetics)
Give some examples of clinical applications of Fick's law
-gas exchange in the lungs between blood and alveoli. THe alvoeli have a large area, contributing to a large flux for molecular oxygen across the membrane.

-In Cystic Fibrosis, the lack of a Cl- ion channel results in the thickening of the alveolar wall, which decreases flux of oxygen through the wall by increasing "x". The increaesd membrane thickness in the alveoli creates a greater distance for diffusion and decreased flux.
Passive transport
does not require energy, ions flow from the side with high concentration to low concentration (down its concentration gradient), regardless of whether it leaves or enters a cell

A. Passive diffusion
B. Bulk flow
C. Facilitated Diffusion
Passive diffusion
eg. when ions go down their concentration gradient through leakage channels (aka pores) to set up the resting potential
Bulk flow
eg. Water going into or out of a cell, which does not require a specific leakage channel since water can diffuse through the membrane (the discovery of aquaporins is changing this view)
Facilitated diffusion
occurs with a uniport non-energy dependent carrier

molecule moves down its concentration gradient
Active transporter
The ATPase pump that uses ATP as a source of energy to pump an ion across a membrane from the side of low concentration to high concentration.
PRIMARY ACTIVE TRANSPORT
Respiratory Pump
Found in mitochondria as part of oxidative phosphorylation; H+ ions flow down their concentration gradient, releasing energy to drive ATP production
Classes of ATPases:
1. P class ATPase
2. V class ATPase
3. F class ATPase
P class ATPase
Na+/K+ pump, or the Ca++ transporter.
pump is dependent on ATPase capability
Ca++ transporter
takes up Ca2+ from the cytosol and stores it against its gradient in the endoplasmic reticulum
V class ATPase
-In vesicles (such as lysosomes)
-store chemicals in high concentrations
F class ATPase
ATP synthase on the inner mitochondrial membrane
Describe the transport occurring in the gut epithelial cell
One end of the gut epithelial cell faces the lumen of the gut (luminal end) and contains a glucose/Na+ symport, and the other end (apial end) leads to the blood stream and has a glucose transport channel as well as a Na/K ATPase. The Na/K ATPase pumps Na+ into the blood and K+ into the cell, giving the epithelial cell a low Na+ concentration and high K+ concentration. The low Na+ in the cell and higher Na+ concentration in the lumen allows for its movement from the lumen into the epithelial cell via the glucose/Na+ symport, which uses that free energy released from Na+ transportation to simultaneously transport one molecule of glucose into the cell from the lumen. This glucose is passively transported into the blood through the glucose transport channel on the apical end if the concentration of glucose in the cell is higher than in the blood.
Why would the brain and the heart use ion channels and not carrier mediated diffusion?
Ion channel maximum rate:
10e6 ions per second – very rapid

Transporter maximum rate:
10e3 ions per second
The fastest an ion can be transported is:
Simple diffusion.

For reference:
Ion channel maximum rate:
10e6 ions per second – very rapid

Transporter maximum rate:
10e3 ions per second
Pore
aka NONGATED CHANNEL
aka LEAKAGE CHANNELS

The number and type of pore channels are responsible for the RESTING MEMBRANE POTENTIAL
Resting membrane potential
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential.

The ion concentrations dictate the direction of ion flux, the sign of the Vm (positive or negative) and the
value of the Vm. All of these factors play into what determines the electrochemical equilibrium (EEq).
An EEq is achieved when the diffusion of an ion (determined by Fick’s law) is in equilibrium with the
electrostatic attractions of that ion. Note that, even in equilibrium, ions are still moving, so there’s still a
flux. The difference with equilibrium states is that there’s no net flux. The EEq results in an equilibrium
potential (EP) that can be described mathematically with the Nernst equation. The EP only applies when
only 1 ion is permeable across a membrane; with multiple permeable ions, the equilibirum is destroyed
and EP is replaced with a resting membrane potential (RMP).
Mechanical gated
stretch in the membrane can physically open the channel
Water channels
Aquaporins
Temperature gated
Gated channels that open at certain temperatures
What is ion channel selectivity based on?
K+, Na+, and acetylcholine receptor channels each have unique sizes. However, based on size alone, it is unlikely that you can get enough specificity for certain ion species. Ions are proposed to function as "hybrids" in that they use size AND loose interior binding sites to select for ions. Channels bind some molecules on their interior, but not others. Sometimes, H20 must come off the molecules in order to get in as well. As channels are proteins with defined amino acid sequence, an alteration of the few specific amino acid residues of the channel can change the specificity of the channel and affect the permeability of the membrane for an ion.
Why would you want gap junctions in the heart?
Gap junctions are abundant in heart tissue where the electrical signal to the different parts of the heart must be conducted rapidly to ensure that all the cells of the atria or the ventricles
Passive diffusion across a cell membrane differs from facilitated diffusion in that:
A. facilitated diffusion is not dependent on a concentration gradient
B. Facilitated diffusion requires energy from the hydrolysis of ATP
C. facilitated diffusion cannot be competitively inhibited
D. Facilitated diffusion allows the passage of only small, lipid soluble molecules
E. Facilitate diffusion exhibits a transport maximum
E. Facilitate diffusion exhibits a transport maximum
Molecule “x” moves into the cell by simple diffusion. Which of the following factor(s) would decrease the flux of “x” into the cell?
A. an increase in the intracellular concentration of “x”
B. an increase in temperature
C. a decrease in the thickness of the membrane
D. an increase in the extracellular concentration of “x”
E. an increase in the partition coefficient of “x”
A. an increase in the intracellular concentration of “x”
Circuit: Cell
Wire carrying current: w
Battery that induces current: x
Capacitor: y
Resistor: z
Circuit: Cell
Wire carrying current: intracellular and extracellular ionic fluid
Battery that induces current: electromotive force is the ion gradient established through electrochemical equilibrium
Capacitor: cell membrane
Resistor: phospholipids with fixed resistance and transmembrane proteins-ion channels- which serve as variable resistive elements when they open and close
Voltage
Electric potential difference between two points

Ben Franklin defined current as being carried by POSITIVE CHARGE FLOWING TO A NEGATIVE POLE .. ie. IT WILL FLOW FROM AN AREA OF HIGH VOLTAGE TO LOW VOLTAGE
Current (I)
flow of electric charge through a conductive medium

Ben Franklin defined current as being carried by POSITIVE CHARGE FLOWING TO A NEGATIVE POLE .. ie. IT WILL FLOW FROM AN AREA OF HIGH VOLTAGE TO LOW VOLTAGE
Common properties of ion channels which make up the electrical "ID card" of the channel:
1. The amount of current that can flow depends on the voltage applied and an intrinsic property called "the conductance"

As channels open and close continuously upon activating stimuli, the other important characteristics are:
2. How long the channel stays open (on average called the "mean operating time"
3. How long are the average closing intervals representing the "frequency of opening" of the channel
4. The "selectivity" of the channel for ions
Conductance

how can you calculate it?
units?
G
A measure of a material's ability to conduct electric charge; the reciprocal of the resistance.
In terms of cellular physiology, it is more useful to think of resistance in an opposite manner, that is, in terms of conductance. It is more beneficial to see how much current will be flowing through a resistance than to measure how much will not.

G=1/R
where R is resistance

I=GV
current = conductance * voltage

Units? Siemens

**REMEMBER THAT CONDUCTANCE IS ALWAYS A POSITIVE VALUE.
Mean operating time
How long a channel stays open on average
Frequency of opening
How long are the average closing intervals for a channel
What is the resting membrane potential of a cell due to?
The presence of leak channels

(which are selective for particular ions -- like Na+ and K+-- and of impermeable intracellular protein anions)
Ohm's law
V=IR

In terms of cellular physiology, it is more useful to think of resistance in an opposite manner, that is, in terms of conductance. It is more beneficial to see how much current will be flowing through a resistance than to measure how much will not.

Thus, since G = 1/R, you can rewrite it as:

I=GV

where
V=voltage (in volts) ** note that V in the second equation is really (V-E) where V is the voltage applied and E is the Nernst potential of the ion channel. If the voltage applied is equal but opposite the Nernst potential, V-E= 0 and there will be no current
I=current (in amperes)
R=resistance (in ohms)
G= conductance (in Siemens)
In a cell, current is carried by?
CATIONS (Na+, K+, Ca++) which move in the same direction as the current itself.

Anions, like electrons, move in the opposite direction making a negative current.
Capacitance
-what is it
-how do you calculate it
-normal value in the body?
-what does it refer to in the body?
The ability of a circuit element to store charge

C=q/V

Where
V= voltage (in volts)
q= charge (in columbs)
C = capacitance (farads F)

Normal capacitance in the body: pF (10^-12 F)

Capacitance pertains to a cell membrane, because it has the ability to store charge. Circuit elements, called capacitors, are made from two parallel conductive plates, separated by an insulator. In a cell, the membrane lipids which make up the bilayer serve as the insulator, and the two parallel plates are represented by the ion-containing solution on either side.

**CAPACITANCE DECREASES WITH THE DISTANCE BETWEEN PLATES (MEMBRANE THICKNESS) AND INCREASES WITH THEIR SIZE (CELL SIZE).
Voltage:
a. units
b. physiological value
a. Volts (V)
b. 10^-3 V, mV
Current:
a. units
b. physiological value
a. Amperes (A)
b. 10^-12 A, pA
Resistance:
a. units
b. physiological value
a. Ohm's (upside down horseshoe)
b. 10^6 ohms, MOhms

**RESISTANCE DEPENDS ON THE NUMBER OF CHANNELS AVAILABLE**
Conductance:
a. units
b. physiological units
a. Siemens (S)
b. 10^-9 S, nS
What is a typical cell's resting membrane potential? What happens to it after an action potential?
A typical cell's resting membrane potential is -70 mV to -90 mV, while an action potential can depolarize a cell by approximately +120 mV to ~+50 mV.
Capacitance decreases with? Increases with?
**CAPACITANCE DECREASES WITH THE DISTANCE BETWEEN PLATES (MEMBRANE THICKNESS) AND INCREASES WITH THEIR SIZE (CELL SIZE).
Electrochemical equilibrium potential
Nernst equilibrium

Ek = RT/ZF * 2.3 * log (Ko/Ki)

OR, SIMPLIFIED (and at 30C)

Vm = 60 * log ([ion outside]/[ion inside])

where
Ek = equilibrium potential for an ion
R= gas constant
T= absolute temperature
Z= charge (**eg. K+ = +1, Ca2+ = +2, Cl- = -1)
F= Faraday's constant
***Be sure to review the hypothetical glial cell and hypothetical Neural cell from the powerpoint***
***Be sure to review the hypothetical glial cell and hypothetical Neural cell from the powerpoint***
What does it mean when you say that a cell has an equilibrium potential of -70 mV?
This means the intracellular environment has an electrical voltage (potential) 60 mV less than the surrounding extracellular environment.
Conductance v. Permeability?
Although they may be used interchangeably, PERMEABILITY IS A PROPERTY OF THE MEMBRANE. This is the number of channels contained in a membrane. Conductance instead refers to the ELECTRICAL PROPERTY due to the current of ions. If no ions are present, the membrane will still have permeability as the channels are always there, but there is no conductance as there is no current.
How many sodium leak channels are there in comparison to potassium leak channels in a typical neuron?
There are approximately 1 Na+ leak channels for every 100 K+ leak channels
In a neuron, the effect of the influx of Na+ will depolarize the cell. As a result, the flow of K+ back into the cell driven by electrical gradient will be diminished while the flow of K+ out of the cell driven by the concentration will remain the same. The result of this is???
1. The potassium electrochemical equilibrium is destroyed (RMP is not at Ek anymore)
2. A net K+ current moving outside the cell (Ik) is created
3. Net Na+ current moving inside the cell (Ina) is created

This will continue until the cell reaches a steady state where Ik + Ina = 0 **this is the fundamental condition that determines resting membrane potential
Depolarize essentially means
make less negative
In a normal cell at the resting membrane potential the concentration gradient or ions inside and outside the cell is maintained by?
The Na+/K+ pump!! This pump will hyperpolarize the cell slightly, because of the electrogenic property of the pump (recall it pumps 3 Na+ out and 2 K+ in) determining a net outward current.
Steady State
Ik + Ina + Icl = 0

*** RESTING MEMBRANE POTENTIAL
determined by goldman-hodgkin-katz equation or conductance equation
The membrane potential is created by __ and maintained by __.
THE MEMBRANE POTENTIAL IS CREATED BY THE LEAK K+ CHANNELS BUT IS MAINTAINED BY NA+/K+ ATPASE.
What is the primary means by which cells alter their resting potential?
By changing the number of leak channels in their membrane.
oubain
(pronounced wa-bane)
a toxin
potent inhibitor of Na+/K+ ATPase.
By binding to the a-subunit it inactivates the pump, causing the membrane to depolarize.
Suppose we could add sodium leak channels and suddenly the membrane becomes more permeable to sodium. What happens to the resting membrane potential? What if the membrane suddenly became permeable to an anion?
Na+ will flow down its concentration gradient into the cell making it less negative. However, potassium leak channels are always present and they will increase the flux to try to compensate the Na+ influx.

Conversely, if the membrane become suddenly permeable to an anion that is not very abundant inside the cell, the membrane potential becomes more negative, or hyperpolarized.
How to measure RMP:
In reality, cells are permeable to many ions, not just one (cough Fick's law cough) and determining the resting potential requires

EQUATIONS:
1. The Goldman-Hodgkin-Katz (GHK) Equation
2. The Conductance Equation


Technically, you can stick a cell with a glass pipette with a wire in it and connect it to a voltmeter, but this isn't really practical, esp if you just want to predict stuff.
The Goldman-Hodgkin-Katz (GHK) Equation
-used to measure RMP
-Vm = RT/ZF * ln (Pna*[Na+]o + Pk*[K+]o + Pcl*[Cl-]i) / (Pna*[Na+]i + Pk*[K+]i + Pcl*[Cl-]o

Looking at the GHK equation we can see that the extracellular cation concentrations in the numerator and intracellular concentrations in the denominator, while for the anions the opposite is true.

P is the equilibrium potential
(ala 60/z*log([ion out]/[ion in])

The GHK Equation is not very easy to use in practice as it requires us to measure the permeability for all the ion species involved. This is typically done using radioactive ions and measuring the amount of radioactivity inside cells. --> The conductance equation provides a very simple means to determine RMP as it just requires one to measure electrical properties like voltage and current.
The Conductance Equation
-used to measure RMP
-Based on the Ohm's law for membranes

Vm = (Ek*Gk + Ena*Gna) / (Gk + Gna)

where
Ek is the equilibrium potential (ala = 60/z*log([ion out]/[ion in])

The GHK Equation is not very easy to use in practice as it requires us to measure the permeability for all the ion species involved. This is typically done using radioactive ions and measuring the amount of radioactivity inside cells. --> The conductance equation provides a very simple means to determine RMP as it just requires one to measure electrical properties like voltage and current.
Ohm's Law for Membranes
I = G(Vm-Erev)

where I = current for an ion
G= conductance for the ion
uhm...
Describe how ions move through a channel.
When an ion channel is open the ion will move down its concentration gradient; however, because ion channels have selectivity filers (allowing only certain ions through) they do not follow the general diffusion rules set by Fick's Law at high concentrations. This is seen when there is a high concentration causing saturation of the selectivity filter; this is not seen in physiological conditions.
Hyperpolarization
a change in a cell's membrane potential that makes it more negative.

Hyperpolarization is the opposite of depolarization, and inhibits the rise of an action potential.
.Depolarization
a change in a cell's membrane potential, making it more positive, or LESS NEGATIVE. In neurons and some other cells, a large enough depolarization may result in an action potential.

-depolarization of the action potential is caused by the OPENING OF VOLTAGE GATED NA+ CHANNELS that allow Na+ to rush into the cell, making the membrane potential less negative to a positive maximum called "overshoot"
What is the difference between equilibrium and steady state?
The difference between equilibrium and steady state is ENERGY CONSUMPTION:
An equilibrium potential is able to maintain its own gradient but an RMP needs to utilize energy to avoid dissipation of the gradient.
Define electrochemical equilibrium
Achieved when the diffusion of an ion (determined by Fick's law) is in equilibrium with the electrostatic attractions of that ion. This results in an EQUILIBRIUM POTENTIAL (= 60/z*log [ion out]/[ion in])
Define reversal potential
THE POTENTIAL AT WHICH THE CURRENT CHANGES DIRECTION
Describe the Nernst equation and how it predicts a potential across the membrane.
Nernst's equation will give you the value of the equilibrium potential.
Used when the membrane is only permeable to only one ion.

Nernst equilibrium

Ek = RT/ZF * 2.3 * log (Ko/Ki)

OR, SIMPLIFIED (and at 30C)

Vm = 60 * log ([ion outside]/[ion inside])

where
Ek = equilibrium potential for an ion
R= gas constant
T= absolute temperature
Z= charge (**eg. K+ = +1, Ca2+ = +2, Cl- = -1)
F= Faraday's constant
Define a resting potential and describe how it is measured.
Ik + Ina + Icl = 0

determined by goldman-hodgkin-katz equation

Vm = RT/ZF * ln (Pna*[Na+]o + Pk*[K+]o + Pcl*[Cl-]i) / (Pna*[Na+]i + Pk*[K+]i + Pcl*[Cl-]o


or

conductance equation

Vm = (Ek*Gk + Ena*Gna) / (Gk + Gna)
where
Ek is the equilibrium potential (ala = 60/z*log([ion out]/[ion in])
How does the Goldman-Hodgkin-Katz equation differ from the Nernst equation?
GHK takes into account the fact that cells are permeable to many ions. Otherwise they're pretty similar. In fact, if there are no other ions present that are permeable, their respective terms cancel out and you're left with just the one ion ala the nernst equation.
current clamp
you're controlling the current and measuring the voltage.
the voltage clamp is more technically demanding than a current clamp but more informative as well as it gives data on the conductance changes v. time.

patch clamps are a special type of voltage clamps
voltage clamp
-technique that allows one to hold the membrane voltage at a fixed value and to keep it there, even when conductance is changing. Any change in current is a direct result of a change in conductance.
-the value of this is that you can set the voltage to a pre-determined value and then observe what currents are entering or leaving the cell.
-stick a tiny wire inside a squid giant axon and connect it to a feedback amplifier. The amplifier rapidly senses any voltage change and corrects the potential to match the command potential (experimentally set voltage).
-has the advantage of being able to study current by applying a constant voltage, and this method eliminates the effects of capacitance
-can bypass the time constant in a voltage clamp

***you're controlling the voltage and measuring the current. because the voltage cannot change, any change in current is a direct result of a change in conductance ***
Which of the following factors is NOT required to determine the current generated by an ion as it moves through a channel?

A. The equilibrium potential for that ion
B. The membrane potential
C. The conductance of the channel
D. Ohm’s law for the cell membrane
E. The capacitance of the membrane
E. The capacitance of the membrane
In the electrical circuit analog, the driving force for movement of an ion across a membrane is:
A. dQ.dt where Q= the charge of the ion and t=time
B. The nernst equilibrium potential for that ion
C. The difference between the membrane potential and the equilibrium potential for the ion
D. The inverse of resistance
E. RmCm
C. The difference between the membrane potential and the equilibrium
Select the FALSE statement about ion channels

A. flux of an ion through a channel is a non-linear function of ion concentration
B. channels can be selective for one or more ions
C. channels are transmembrane spanning proteins
D. A channel can be described as a water or fluid-filled pore
E. flux of an ion though a channel is slower than the flux via a transporter (carrier).
E. flux of an ion though a channel is slower than the flux via a transporter (carrier).
Patch clamp
-variant of the voltage clamp
-allows us to voltage clamp a tiny piece of membrane, a membrane "patch," to study the current produced by a SINGLE CHANNEL ACTIVITY.
-the patch can be still attached to the cell (cell attached) or excised in different recoding arrangements (inside-out or outside out)

This image shows an example of a sodium channel voltage clamp graph. Time is on the X axis and current on the Y axis.
the seven trace recording depict the opening characteristics of one channel. Notice that the channel opens at different times in each trace, and the AVERAGE of all seven is shown at the bottom. This average recording is the key because the macroscopic current we see in the cell is the result of the summed average of the currents of many thousands of channels.
Action potential
-produced in excitable cells such as neurons, skeletal muscle, smooth muscle, secretory cells, etc.
-the change in voltage characterized by a change in threshold, depolarization, repolarization
- have an OVERSHOOT (how much greater than 0 the membrane potential grows) and undershoot (how much more – it is than the resting potential)
- action potential used by somatic nervous system to control skeletal muscle, autonomic nervous system, sympathetic and parasympathetic nervous systems, brain cells
-action potentials are unidirectional
-action potentials are all or nothing
Once initiated, the amplitude of each action potential ____.
Once initiated, the amplitude of each action potential will always be the same.
overshoot
how much greater than 0 the membrane potential grows
undershoot

What is it due to?
a slight hyperpolarization at the end of the action potential

more negative than the resting potential

undershoot is due to the persistant activation of potassium channels which keep the cell hyperpolarized longer than it would normally be.
Voltage gated Na+ channels inactivate at about the same time that ____.
Voltage gated Na+ channels inactivate at about the same time that -- delayed rectifier voltage gated K+ channels open, initiating the repolarization phase.--
Repolarization
The return of the membrane potential to the resting potential

Voltage gated Na+ channels inactivate at about the same time that delayed rectifier voltage gated K+ channels open, initiating the repolarization phase.
The opening of the delayed rectifier voltage gated K+ channels allows K+ tgo flow out of the cell, returning the membrane potential back to the resting membrane potential or slightly below.
The RMP of most cells is closest to the Nernst equilibrium for __. Why?
The RMP of most cells is closest to the Nernst equilibrium for K+ rather than Na+. This is because the cell membrane has a higher permeability for K+ (greater number of K+ than Na+ leak channels) and therefore K+ has the greatest impact on the overall resting potential (Vm).
Vm
overall resting potential
threshold
the voltage at which an action potential can start

(or put another way)

the value of the membrane potential which, if reached, leads to the all-or-nothing initiation of an action potential
excitable cells
cells that display action potentials: heart, muscle, nerve

tend to have a lot of voltage gated Na+ channels
The voltage at the peak of the action potential is close to the equilibrium potential of what ion? Why?
The voltage at the peak of the action potential is close to the equilibrium potential of Na+, Ena. This is because when the threshold is reached and voltage gated Na+ channels begin to open, the permeability for Na+ goes way up because excitable cells (heart muscle nerve) typically have lots of these channels.
When does the action potential officially begin?
Whenever the membrane potential reaches threshold the AP takes off in a rapid, self-sustaining manner. The current entering through the sodium channels is sufficient all by itself to continue the depolarization in a regenerative cascade of positive feedback.
Label.
Also talk about the sequence of events in an action potential.
The sequence of events in an action potential are:
1. Membrane depolarization opens voltage gated sodium channels
2. Sodium rushes into the cell
3. The cell depolarizes which helps to open more sodium channels
4. Membrane potential is driven up to Erev for sodium -- this limits the duration of the action potential in two ways:
A. sodium channels inactivate which causes a decrease in Gna
B. Depolarization opens voltage gated potassium channels to increase Gk
5. Potassium rushes out to repolarize the cell
6. Local circuit currents are produced during an action potential which allow spreading (propagation) to the near by membrane
7. This could potentially produce a retrograde flow of current (eg. an action potential going the wrong way down an axon. This is prevented by the refractory period)

Even with a small depolarizaition, few voltage gated channels will open and produce a small inward current. The magic happens when the inward current produced by the voltage gated Na+ channel is large enough to counteract the outward current produced by the K+ leakage channel. When this occurs, the current from the inward flow of Na+ causes more depolarizaation of more channels in a positive feedback, explosive manner, generating an action potential.

At the peak of the action potential, the voltage gated Na_ channels inactive and close, the K+ leakage channels begin to repolarize the membrane, and delayed voltage gated K+ channels open allowing faster repolarization of the membrane.

**SPIKE ONLY OCCURS AT THRESHOLD WHEN THE INWARD RUSH OF SODIUM EXCEEDS THE OUTWARD FLUX OF POTASSIUM
Let's talk about these lines/graphs.
First, all the parallel lines on the top portion represent various steps in voltage given one after the other. For each of those (8) parallel lines, there is a corresponding curvy line below. The curvy lines represent the current, and the waveform is complex. Referring back to Ohm's law for the membrane, remember that we can tell the direction of current for each ion if we know the Vm (which we do because it is set as the commant potential) and if we know Enernst (which we assume to be previously determined for a given ion). The Y-axis displays current in mA/cm2, so any line dipping below the 0 line (and with a negative slope) is negative current. Sodium is entering the cell. After a short time, the current changes direction, passes the 0 line, and increases until it reaches a maximal value determined by the command potential. On this graph, an upward current swing indicates a positive current value, and since we're dealing with positive ions, they must be leaving the cell. Also notice the current is changing as a function of time -- this indicates the value of Gna and Gk are changing. Since conductance is always positive, the sign of the current is entirely a function of the sign of the driving force which is given by: (Vm-Ena) for sodium, or (Vm-Ek) for potassium. From this graph we can see that there is an inward and outward current. How can you tell which is which? use an inhibitor for K or Na channels and then measure.
Conductance is always ___.
Since conductance is always positive, the sign of the current is entirely a function of the sign of the driving force which is given by: (Vm-Ena) for sodium, or (Vm-Ek) for potassium.
The sign of the driving force for sodium:
(Vm-Ena)
The sign of the driving force for potassium:
(Vm-Ek)
Fugu
pufferfish

not prepared properly it can be contaminated with tetrodotoxin (TTX) .. causes you to die because it affects not only your heart but, more importantly, your respiratory rate.

TTX is a highly specific blocker of sodium channels
Examples of sodium channel blockers.
Why should you care?
tetrodotoxin (TTX)
saxitoxin (STX)

By utilizing these toxins in experiments with voltage clamps, it is possible to block the sodium current to specifically measure the potassium current in an action potential.

TTX is made by the pufferfish
STX is produced by the algae responsible for the red tide.
Examples of potassium channel blockers. Why should you care?
Tetraethylammonium (TEA)

TEA selectively blocks the outward flow of potassium which makes for easy visualization of both the magnitude and time course of the sodium current in voltage clamp experiments.
Command potential
experimentally set voltage
The time course of the Na or K current depends on?
The time course of the Na or K current depends on the changing probability of opening many channels at once.
The macroscopic current we see in the cell is the result of?
The macroscopic current we see in the cell is the result of the summed average of the currents of many thousands of channels. (in this case, he was talking about the voltage-gated sodium channel)
The voltage-gated sodium channel is most likely to open when?
The voltage-gated sodium channel is most likely to open very quickly after the voltage step is made.
Voltage gated sodium channels are (fast/slow)-opening ion pores?
Voltage gated sodium channels are FAST-opening ion pores.
3 conformations of voltage gated sodium channels:

Why are they important?
3 conformations of voltage gated sodium channels:
1. Open
2. Closed-Inactivated
3. Closed

These characteristics are essential for the propagation of action potentials down an axon.

In the image above, starting at time = 0, a stimulus pulse is given. The voltage gated channel senses this voltage step and opens. Channel opening increases conductance and we see an increase in sodium current. Just after the peak of the current, the channel closes and enters its closed-inactivated state. This confirmation is dependent on both time and voltage. The channel remains INACTIVE until the cell repolarizes and enters its closed confirmation. Together, the closed-inactivated channel and closed channel create a period of time where another spike cannot happen, and is the basis for the REFRACTORY PERIOD, during which, when the channel is closed-inactivated, no spike can happen, regardless of how much the voltage changes. In the closed state, a spike CAN be initiated but it would require a stronger depolarizing stimulus.

**Allows for UNIDIRECTIONAL ACTION POTENTIAL
Reentry
-major cause of cardiac arrhythmia
-due to the electric signal not completing a normal circuit, but rather looping back on itself (ie. if Na+ channels are not inactivated)
Refractory period
i. Absolute
ii. Relative
Can a spike occur when the voltage gated sodium channel is in the closed inactivated state?
NO. This is the basis of the refractory period.

*ABSOLUTE REFRACTORY PERIOD
Can a spike occur when the voltage gated sodium channel is in the closed state?
Yes, but it would require a stronger depolarizing stimulus.

*RELATIVE REFRACTORY PERIOD
Absolute refractory period

What is it due to?
a period of time after the initiation of one action potential when it is impossible to initiate a second action potential no matter how much the cell is depolarized because the sodium channel is closed-inactive
Relative refractory period

What is it due to?
a period after one action potential is initiated when it is possible to initiate a second action potential, but only with a greater depolarization than was necessary to initiate the first.
it is due to the persistent activation of potassium channels which keep the cell hyperpolarized longer than it would normally be.
Compare sodium and potassium channels.
Sodium:
3 conformation:
1. open (RAPID)
2. closed-inactivated
3. closed
*states are dependent on time and voltage.

Potassium:
1. Open (slower than sodium channels)
2. Do not exhibit inactivation -- remain open as long as the cell is depolarized
How long does the sodium channel remain inactive?
Until the cell repolarizes and enters its closed confirmation
Local currents
the loops on the bottom graph indicate the movement of charges.
The Na+ ion current goes to places on membrane on the side and depolarizes them during activation. Tends to depolarize nearby segment to allow conductance to occur.

Recall that action potentials in axons are unidirectional, however, because of voltage gated Na+ channel closed inactivation state.
Can you define threshold for a single channel current?
Nah mate.
Hyperkalemic periodic paralysis
rare inherited disorder characterized by episodes of muscle weakness in one or more limbs and intermittent myotonia(1); often accompanied by elevated serum potassium levels(1)

hyperkalemia - serum potassium > 5.1 mEq/L (5.1 mmol/L) (reference ranges may vary between laboratories)

Organs involved: limb muscles(2); may also effect muscles of eyes, throat or trunk

Caused by mutations in several aa's in the Voltage-gated Na+ channels, resulting in disruption of Na+ channel and muscle fatigue
Paramyotonia congenita
Caused by mutations in several aa's in the Voltage-gated Na+ channels, resulting in disruption of Na+ channel and muscle fatigue
Mutations in the sodium channel are often associated with?
EPILEPSY!

also mentioned:
hyperkalemic periodic paralysis
and
paramyotonia congenita
and
"various neurological disorders"
Clinically relevant Na+ channel blockers?
-cocaine
-2 derivatives of cocaine (used by dentists):
1. lidocaine
2. procaine
Main side effect for cocaine abuser?
Affects cardiac function (cocaine blocks Na+ channels)
Higher than normal extracellular Ca++ causes ____, and lower than normal extracellular Ca++ causes ____.

WHY.
Higher than normal extracellular Ca++ causes DECREASED EXCITABILITY (higher threshold, harder to kick off an action potential), and lower than normal extracellular Ca++ causes HYPEREXCITABILITY (lower threshold, easier to kick off an action potential).

Ca++ plays an important role in the regulation of the voltage gated Na+ channels as it changes the way that the voltage gated Na+ channel senses changes in the membrane potential because of CHARGE SHIELDING EFFECTS on the voltage sensor by calcium. Calcium in the extracellular fluid interacts with the voltage sensor and fools it.

eg. If a depolarizing potential is really -20 mV, with Ca++ present, the channel will sense only -10mV. Therefore when there is a high concentration of Ca++ in the extracellular space, the voltage gated Na+ channels require a larger depolarization in order to reach their threshold and generate an action potential. On the other hand, low Ca++ levels can lead to a perceived membrane potential larger than it really is, requiring a smaller depolarization to reach threshold and hyperexcitability.
Why should you watch a patient's calcium levels?
The nerve may fire at inappropriate times.
Clinically, one of the most important ions to watch when looking at a patient is their calcium levels because a drop of 50% or more may lead to tetany of peripheral nerves. Paralysis of respiratory muscles may result.

(Tetany:
-lowered muscular excitability threshold
-results in involuntary spasms)
hypercalcemia
higher than physiological levels of extracellular Ca++ --> threshold shifted to more depolarized voltage and get decreased excitability
hypocalcemia
lower than physiological levels of extracellular Ca++ --> threshold lowered and you see hyperexcitability
What does this figure depict? What does a right shift correspond to?
The figure above depicts what happens when extracellular calcium is varied. A right shift corresponds to an increase in Ca++, which makes it increasingly harder to initiate an action potential.
Conduction velocity
speed of propagation of action potential (m/s)

differs for different axons depending on:
-axon diameter (larger = faster)
-capacitance
-myelanation
-kinetics of Na+ channel
Passive property of cables

how can you increase the distance of voltage propogation?
-voltage decreases at distance from the current
-happens for any current
-longer distance of voltage propogation when you have better isolation -- ie. increased membrane resistance or when cable is large and well conducting
Space constant

what does increasing the space constant do for you? how can you do this?
symbol = lamda

-deals with how far an action potential can passively travel due to a decrement in voltage
-conceptually, the space constant is THE DISTANCE AN ACTION POTENTIAL CAN TRAVEL BEFORE IT REACHES 37% OF ITS INITIAL STRENGTH.

lambda = sqrt (Rm/Ri)
where
Rm = membrane resistance
Ri=internal resistance given as the inverse of the diameter of the cell (ie. Ri=1/d)

increasing the space constant INCREASES THE SPEED AND DISTANCE AN ACTION POTENTIAL WILL TRAVEL. You can increase the space constant by:
1. increasing the axon diameter, thereby decreasing internal resistance
2. Increasing membrane resistance, thereby reducing the amount of current lost to surroundings. What affects membrane resistance? The properties of phospholipids, the number of leak channels, the presence of myelin.
More myelin =
faster conduction
A nerve with a large diameter is probably functioning to __. How about a small diameter?
Large diameter -- need to conduct as fast as possible.
Small, not as concerned about speed.
What do capacitors do? What acts like a capacitor in our bodies?
Capacitors store charge.
A cell membrane acts as a capacitor by separating and storing the intra and extracellular charge.

Envision a circuit composed of a resistor, a capacitor, and a current source. In a resting state, no current is flowing and the capacitor is initially uncharged (time = 0). To charge it, we flip a switch to complete the circuit. Current will flow and increase the charge on the capacitor plates. If we left the switch closed long enough, eventually the charge would accumulate on the capacitor such that the potential difference would equal the output of the battery and current would stop flowing. The capacitor is now fully charged. During an action potential, this is what happens to the membrane. The flow of ions actually charges the membrane, and by doing so, the action potential becomes weaker. Thus, if we could decrease capacitance (reduce the membrane's ability to steal current from the action potential), it would speed signal propagation.
Time constant
the amount of time required to charge and discharge the membrane capacitance

= Rm*Cm
(or the membrane resistance * membrane capacitance)

Represented by a swirly T.
Reducing capacitance improves
Conduction velocity !

Think of charge that is flowing through the axon as water, and think of capacitance as a series of buckets along the axon. if we use large buckets, it will take a lot of water (charge) to fill one bucket before you can empty it into the next bucket. However, if we use small buckets, it will only take a little bit of water (charge) to fill one bucket so that you can quickly empty it into the next bucket. You may not get much water but you can move the water very quickly.
Name two cell that help to decrease membrane capacitance and increase resistance. How DO they do it?!
1. oligodendrocytes in the CNS
2. Schwann cells in the PNS

-Both wrap axons with myelin.
-successive layers of myelin thicken the membrane and effectively increase the distance between the plates of the capacitor (the intra and extracellular environment)
-these layers also insulate the axon and prevent current loss to the environment.