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Flashcards in Membrane Physiology Deck (19):
1


Membrane Potential
•Transport of ions across the cell membrane leads to ___ distribution of ionic concentrations between extracellular and intracellular fluids, ___ ___ ___

•The membrane potential is critical for signal transduction in excitable cells such as ___ and ___

•To understand how nerves impulses are generated or how muscles are induced to contract, one must first understand the origin of the membrane potential. 


•Transport of ions across the cell membrane leads to unequal distribution of ionic concentrations between extracellular and intracellular fluids, resulting in membrane potential.

•The membrane potential is critical for signal transduction in excitable cells such as nerve and muscle.

•To understand how nerves impulses are generated or how muscles are induced to contract, one must first understand the origin of the membrane potential. 
 

2


Membrane Potential


•The membrane potential is always given as that of ____ compartment relative to the ____compartment (Vm = V___ – V____).

•In excitable cells, a steady electrical potential difference (resting membrane potential) of about __mV is detected. In nonexcitable cells, the potential difference is____

•By convention, the sign of potential difference indicates that the inside of the cell is electrically ____ with respect to the outside.

•Signals that make the cytoplasm more positive than at rest (ie., signals that____ membrane potential) are said to ____ the membrane, and those making it more nee (ie.,_____the membrane potential) are said to_____ the membrane.
 


•The membrane potential is always given as that of intracellular compartment relative to the extracellular compartment (Vm = Vinside – Voutside).

•In excitable cells, a steady electrical potential difference (resting membrane potential) of about –70 mV is detected. In nonexcitable cells, the potential difference is smaller.

•By convention, the sign of potential difference indicates that the inside of the cell is electrically negative with respect to the outside.

•Signals that make the cytoplasm more positive than at rest (ie., signals that decrease membrane potential) are said to depolarize the membrane, and those making it more negative (ie., increase the membrane potential) are said to hyperpolarize the membrane.
 

3


Membrane Potential – the mechanism
•When the positive and negative charges are equally balanced  on each side of the membrane, the membrane is electrically____ and no membrane potential exists

•A membrane potential arises when there is a difference in the electrical charge on the two sides of a membrane, due to slight ____ of positive ions over negative ions on one side and a slight ___ on the other.

•The attractive forces between the separated charges causes them to____ in a thin layer along the __ and ___ ____ of the plasma membrane.

 


•When the positive and negative charges are equally balanced  on each side of the membrane, the membrane is electrically neutral and no membrane potential exists



•A membrane potential arises when there is a difference in the electrical charge on the two sides of a membrane, due to slight excess of positive ions over negative ions on one side and a slight deficit on the other.


•The attractive forces between the separated charges causes them to accumulate in a thin layer along the outer and inner surfaces of the plasma membrane.

 

4


Resting membrane potential (RMP) in cells
•The ions responsible for the generation of the resting membrane potential are ___ ____and  _____,  which___ ___ within the cell. Na+ and K+ can___ ____ the plasma membrane.

•Transport of Na+ and K+ by the pump accounts for only ___% of the movement of these ions across the membrane. Majority of the movement occurs through “___ ____"

•There are more ___channels than ___channels, allowing more diffusion of K+ than Na+. At resting potential in a nerve cell, the membrane is typically about ______ times more permeable to K+ than to Na+. The ___ ____ of the plasma membrane to ___ ___ contributes significantly to the generation of the membrane potential.

••





 


•The ions responsible for the generation of the resting membrane potential are Na+, K+, and the large negatively charged intracellular proteins which remain trapped within the cell. Na+ and K+ can move across the plasma membrane.

•Transport of Na+ and K+ by the pump accounts for only 10% of the movement of these ions across the membrane. Majority of the movement occurs through “leaky channels”.

•There are more K channels than Na channels, allowing more diffusion of K+ than Na+. At resting potential in a nerve cell, the membrane is typically about 25 to 30 times more permeable to K+ than to Na+. The differential permeability of the plasma membrane to these ions contributes significantly to the generation of the membrane potential.

••





 

5


Ionic mechanisms of RMP

 

 

Ion

ECF Concentration (mM)

ICF Concentration (mM)

Permeability

Na+

150

15

1

K+

5

150

25-30

Pro-

0

65

0

6

If we consider the movement of K+ ions alone:

•If it is assumed that K+ ions are freely permeable, with no restrictions to its movement, then K+ ions will move back and forth across the membrane.

•Two forces will drive the movement of K+ across the membrane: (1) ___ driving force that depends on the _____ ____ across the membrane and (2) an ____ driving force that depends on the _____ ____ ____ across the membrane.

•Once K+ diffusion has proceeded to a certain point, a potential develops across the membrane at which the electrical force driving K+ ___ the cell ___ ____ the chemical force driving K+ ions ___of the cell. That is, the outward movement of K+ (driven by its concentration gradient) is equal to the inward movement of K+ (driven by the electrical potential difference across the membrane).

•This potential is called the ____ ___ _____ EK+. The value of the voltage across the membrane for the Equilibrium Potential of K+ = ____ 

7

If we consider the movement of Na+ ions alone:

If it is assumed that Na+ ions are freely permeable, with no restrictions to its movement, then Na+ ions will move back and forth across the membrane until the Electrochemical Gradient has Equilibrated. The value of the voltage across the membrane for the Equilibrium Potential of Na+ = ___ 

If these ions were both equally permeable, then the RMP would be somewhere ___ ___ these two values (in between -90 and +60 mV). However, K+ ions are 25-30 times more permeable than Na+ and therefore the RMP is much closer to the ___ than the ___. The value of -70 mV is much closer to -90mV than to +60 mV.

8


Changes in membrane potential


•Alteration in membrane ____ to key ions (through ___ ___) by a___ due to increased movement of ions and ____ __ ____ across the membrane causes the ___ ____to ____

•If the net inward flow of positively charged ions increases with respect to the resting state (such as more _______), the membrane becomes____ negative inside and the membrane potential ___ – known as ____.

•When the membrane returns to resting potential after depolarization, this is called ____

•In contrast, if the net outward flow of positively charged ions increases with respect to the resting state (such as ______), the membrane becomes ___ negative inside and the membrane potential ____ – known as _____


 


•Alteration in membrane permeability to key ions (through gated channels) by a stimulus due to increased movement of ions and redistribution of charge across the membrane causes the membrane potential to fluctuate.

•If the net inward flow of positively charged ions increases with respect to the resting state (such as more Na+ moving in), the membrane becomes less negative inside and the membrane potential decreases – known as depolarization.

•When the membrane returns to resting potential after depolarization, this is called repolarization.

•In contrast, if the net outward flow of positively charged ions increases with respect to the resting state (such as more K+ moving out), the membrane becomes more negative inside and the membrane potential increases – known as hyperpolarization.


 

9


A typical action potential in neurons


•Resting potential of -70 mV.
•Depolarization proceeds ___ until it reaches a critical level known as ___ ____ (between   ___ and ___mV).
•At threshold potential, an ____ depolarization takes place. Peak potential is usually __ to ___mV depending on the cell.
•Just as rapidly, the membrane ____, dropping back to resting potential.
•Often, the forces that repolarize the membrane push the potential too far, causing a brief after ____, during which the inside of the membrane briefly becomes ____ negative than normal (e.g. -80mV) before the resting potential is restored.
•Thus, the action potential is the entire rapid change in potential from ___ to____and then back to ___ ___.
 


•Resting potential of -70 mV.
•Depolarization proceeds slowly until it reaches a critical level known as threshold potential (between    -50 and -55mV).
•At threshold potential, an explosive depolarization takes place. Peak potential is usually +30 to +40 mV depending on the cell.
•Just as rapidly, the membrane repolarizes, dropping back to resting potential.
•Often, the forces that repolarize the membrane push the potential too far, causing a brief after hyperpolarization, during which the inside of the membrane briefly becomes more negative than normal (e.g. -80mV) before the resting potential is restored.
•Thus, the action potential is the entire rapid change in potential from threshold to peak and then back to resting potential. 
 

10

Explaining an action potential using properties of voltage-gated Na+ and K+ channels


•The membranes contain many different types of gated ion channels. Some of these are____gated and others are ____-gated. It is the behavior of these channels, and particularly Na+ and K+ channels, which explains the ___ events in neurons.

•Action potentials take place as a result of the triggered____ and subsequent ___ of two specific types of channels: ____ and ____

•Both voltage gated Na+ and K+ channels open when the membrane is_____. Opening of voltage-gated K+ channels is ___ and more ____ than the opening of the Na+ channels.



 


•The membranes contain many different types of gated ion channels. Some of these are voltage-gated and others are ligand-gated. It is the behavior of these channels, and particularly Na+ and K+ channels, which explains the electrical events in neurons.

•Action potentials take place as a result of the triggered opening and subsequent closing of two specific types of channels: voltage gated Na+ channels and voltage gated K+ channels.

•Both voltage gated Na+ and K+ channels open when the membrane is depolarized. Opening of voltage-gated K+ channels is slower and more prolonged than the opening of the Na+ channels.



 

11

Voltage-gated Na+ and K+ channels


•Voltage-gated Na+ and K+ channels go through various conformations during the action potential.

•The voltage gated Na+ channel goes through three different confirmations:
1.
2.
3.

•The voltage gated K+ channel is simpler and goes through two confirmations only:
1.
2.

      


•Voltage-gated Na+ and K+ channels go through various conformations during the action potential.

•The voltage gated Na+ channel goes through three different confirmations:
1.Closed but capable of opening (activation gate closed, inactivation gate open)
2.Open or activated (both gates open)
3.Closed and not capable of opening or inactivated (activation gate open, inactivation gate closed).

 

•The voltage gated K+ channel is simpler and goes through two confirmations only:
1.Closed
2.Open (because  it only has an activation gate which can be either closed or open).

      

12

Generation of an action potential


1.Resting potential – Both Na+ and K+ channels are ___
2.In response to a depolarizing stimulus, some of the voltage-gated Na+ channels open and Na+ ____ the cell and the membrane is brought to its_____ potential of ____
3.This causes the ___ of ___voltage-gated___ channels and further ____, setting up a ____ feedback loop. The rapid ____ in the membrane potential ensues – ___ phase. The membrane potential moves toward the ___________ (____) but does not reach it during the action potential, primarily because the increase in __ _____ is ____ ____ Membrane potential reaches about _____
4.The Na+ channels rapidly enter a ___ ____ (the inactivation gate ____) called the ___ ____and remain in this state for a __ ____ before returning to the resting state, when they again can be activated.

In addition, the___ of the electrical gradient for Na+ is reversed during the overshoot because the membrane potential is ____ and this limits Na+ influx;

also the voltage-gated K+ channels ___. These factors contribute to _____.

Because the opening of voltage-gated K+ channels is ___ and more ____ than the opening of the Na+ channels, much of the increase in K+ conductance comes___ the increase in Na+ conductance.

5.The net movement of positive charge ___ of the cell due to K+ efflux at this time repolarizes the membrane – ___ phase.
6.Once the membrane potential reaches the ____________, ___ __ __ ____and _____ gate ____ resetting the channel to respond to another depolarizing stimulus.
7.The slow return of the K+ channels to the closed state explains the __________ (to ~-80 mV).
8.K+ activation gate____s and membrane returns to resting potential.

 


1.Resting potential – Both Na+ and K+ channels are closed.
2.In response to a depolarizing stimulus, some of the voltage-gated Na+ channels open and Na+ enters the cell and the membrane is brought to its threshold potential of -50 mV.
3.This causes the opening of more voltage-gated Na+ channels and further depolarization, setting up a positive feedback loop. The rapid upstroke in the membrane potential ensues – rising phase. The membrane potential moves toward the equilibrium potential for Na+ (+60 mV) but does not reach it during the action potential, primarily because the increase in Na+ conductance is short-lived. Membrane potential reaches about +30 mV.
4.The Na+ channels rapidly enter a closed state (the inactivation gate closes) called the inactivated state and remain in this state for a few milliseconds before returning to the resting state, when they again can be activated. In addition, the direction of the electrical gradient for Na+ is reversed during the overshoot because the membrane potential is reversed, and this limits Na+ influx; also the voltage-gated K+ channels open. These factors contribute to repolarization. Because the opening of voltage-gated K+ channels is slower and more prolonged than the opening of the Na+ channels, much of the increase in K+ conductance comes after the increase in Na+ conductance.
5.The net movement of positive charge out of the cell due to K+ efflux at this time repolarizes the membrane – falling phase.
6.Once the membrane potential reaches the resting potential (-70 mV), Na+ activation gate closes and inactivation gate opens, resetting the channel to respond to another depolarizing stimulus.
7.The slow return of the K+ channels to the closed state explains the after-hyperpolarization (to ~-80 mV).
8.K+ activation gate closes and membrane returns to resting potential.

 

13

Refractory period


•Only when the Na+ channel has reset to its “______________ “ state, it can be re-stimulated to open again. Therefore, when a particular patch of axonal membrane is undergoing an action potential, it can not initiate another action potential, no matter how ____ the depolarizing event is. This period when the recently activated region of axonal membrane is completely refractory (unresponsive) to further stimulation is known as the___ ___ ____

•The absolute refractory period corresponds to the period from the time the _____ level is reached until _____ is about __/___complete.

•Following the absolute refractory period is a ___ ___ ___, during which a second action potential ____ be produced only by a triggering event considerably ____ than usual.

•The relative refractory period occurs after the action potential is completed because :
1.The voltage gated Na+ channels that opened during the action potential do not all ___  __ ____when the resting potential is reached. Some __ ____ to reach their (closed but capable of opening conformation).  As a result, ____ voltage gated Na+ channels are available to be activated in response to another depolarizing event which leads to less than usual Na+ entry in response to a depolarizing event.
2.The voltage gated K+ channels that opened at the peak of the action potential are___  to ___. So, during this time, the resulting less-than-usual Na+ entry in response to another triggering event is ____ by K+ still ____ through its slow-to-close channels during the after hyperpolarization stage.



 


•Only when the Na+ channel has reset to its “closed and capable of opening “ state, it can be re-stimulated to open again. Therefore, when a particular patch of axonal membrane is undergoing an action potential, it can not initiate another action potential, no matter how strong the depolarizing event is. This period when the recently activated region of axonal membrane is completely refractory (unresponsive) to further stimulation is known as the Absolute Refractory Period. 

•The absolute refractory period corresponds to the period from the time the firing level is reached until repolarization is about one-third complete.

•Following the absolute refractory period is a Relative Refractory Period, during which a second action potential CAN be produced only by a triggering event considerably stronger than usual.

•The relative refractory period occurs after the action potential is completed because :
1.The voltage gated Na+ channels that opened during the action potential do not all reset at once when the resting potential is reached. Some take longer to reach their (closed but capable of opening conformation).  As a result, fewer voltage gated Na+ channels are available to be activated in response to another depolarizing event which leads to less than usual Na+ entry in response to a depolarizing event.
2.The voltage gated K+ channels that opened at the peak of the action potential are slow to close.  So, during this time, the resulting less-than-usual Na+ entry in response to another triggering event is opposed by K+ still leaving through its slow-to-close channels during the after hyperpolarization stage.



 

14

 

The action potential is “all or none” in character

Duration of an action potential can be variable for a given cell

Decreasing the external Na+ concentration greatly affects resting and action potentials    

In an individual with hyperkalemia (increased extracellular K+ concentration), the neurons are more excitable

A large number of ions need to move across the membrane to bring about a change in membrane potential

 

The action potential is “all or none” in character

True - If the initial triggered depolarization does not reach threshold potential, no action potential takes place but stronger stimulus does not produce a  larger action potential. A stronger stimulus generates a greater number of action potentials per second. 

Duration of an action potential can be variable for a given cell

False - Duration of an action potential is always the same in a given excitable   cell.

Decreasing the external Na+ concentration greatly affects resting and action potentials    

False - Decreasing the external Na+ concentration reduces the size of the action potential but has little effect on the resting membrane potential. Since the permeability of the membrane to Na+ at rest is relatively low, Na+ does not greatly influence resting membrane potential. 

In an individual with hyperkalemia (increased extracellular K+ concentration), the neurons are more excitable

True – When the external K+ goes up, less K+ will move out through the leak   channels and therefore the resting potential moves closer to the threshold for eliciting an action potential, thus the neuron becomes more excitable.

A large number of ions need to move across the membrane to bring about a change in membrane potential

False – It has been estimated that only 1 in 100,000 K+ ions cross the membrane to change the membrane potential from +30 mV (peak of the action potential) to –70 mV (resting potential)

15

Propagation of an action potential


•Action potentials are propagated from the ___ ___ to the ___ ____

•The axon hillock has the___ threshold in the neuron because this region has a much___ ____of voltage gated ___ Channels than anywhere else in the neuron. For this reason, the axon hillock is considerably ____ responsive than ___or reminder of____ ____ to changes in potential and is the ____ to reach threshold. Therefore, an action potential originates in the axon hillock and is propagated from there to the axon terminals.

•Once an action potential is initiated in one part of a neuron’s cell membrane, a self-propagating cycle is initiated so that the action potential is ___ along the rest of the nerve fibeR ____

•The original action potential does __ travel along the membrane. Instead, it ___ an identical new action potential in the bordering area of the membrane , with this process being repeated along the axon’s length.

 


•Action potentials are propagated from the axon hillock to the axon terminals

•The axon hillock has the lowest threshold in the neuron because this region has a much higher density of voltage gated Na+ channels than anywhere else in the neuron. For this reason, the axon hillock is considerably more responsive than dendrites or reminder of cell body to changes in potential and is the first to reach threshold. Therefore, an action potential originates in the axon hillock and is propagated from there to the axon terminals.

•Once an action potential is initiated in one part of a neuron’s cell membrane, a self-propagating cycle is initiated so that the action potential is propagated along the rest of the nerve fiber automatically.

•The original action potential does not travel along the membrane. Instead, it triggers an identical new action potential in the bordering area of the membrane , with this process being repeated along the axon’s length.

 

16


•Action potentials are spread by ____ ____or the ___ ___of voltage ____ along the membrane of the axon.
•When an action potential occurs at the trigger site (__ ____) positive charges rush ___ the cell.
•This creates a local zone in both the ____r and __ fluid where there is a ___ ____e in charge.
•The positive charges move toward areas of high concentration of ____  Charges.
•This results in a ____ that reaches ____ and continues the action potential. 
 


•Action potentials are spread by electrotonic conduction or the passive spread of voltage change along the membrane of the axon.
•When an action potential occurs at the trigger site (axon hillock) positive charges rush into the cell.
•This creates a local zone in both the extracellular and intracellular fluid where there is a sudden change in charge.
•The positive charges move toward areas of high concentration of negative charges.
•This results in a depolarization that reaches threshold and continues the action potential. 
 

17

Refractory period ensures unidirectional propagation of action potential

Refractory period ensures unidirectional propagation of action potential

18

Graded Potential


•A graded potential is a ___ change in the potential that is ____l (graded) to the ___ of the stimulus causing the change. The stimulus may be a ____r or a ____ stimulus.

•A graded potential can only travel a ____ distance because the change in voltage spreads by the ___ ____ of ions in a process called e____ _____. As the current moves further from the site of stimulation, the membrane potential ____ because the ions ____ and the ions pass through____ in the membrane. Therefore, the change in membrane potential that is due to electrotonic conduction is _____(____).

•Graded potential is ____ (no ___ ____).
 

Graded Potential


•A graded potential is a small change in the potential that is proportional (graded) to the strength of the stimulus causing the change. The stimulus may be a neurotransmitter or a sensory stimulus.










•A graded potential can only travel a short distance because the change in voltage spreads by the passive movement of ions in a process called electrotonic conduction. As the current moves further from the site of stimulation, the membrane potential decreases because the ions diffuse and the ions pass through channels in the membrane. Therefore, the change in membrane potential that is due to electrotonic conduction is decremental (decreasing).

•Graded potential is bidirectional (no refractory period).
 

19

Membrane Potential and Cancer

Potential and proliferation. In a normal, nonproliferating cell, the resting membrane potential (Vm ≈ ____ mV) is set by__ ____activity. ______ lipids are in small clusters that localize with ___, which leads to l___ ____ of the _________ pathway. Channel ____ ______ the cell (Vm ≈ ____), ____ the ____ of phosphatidylserine and K-Ras. This promotes RAF-MAPK signaling ____ cell ____

Potential and proliferation. In a normal, nonproliferating cell, the resting membrane potential (Vm ≈ −50 mV) is set by ion channel activity. Phosphatidylserine lipids are in small clusters that localize with K-Ras, which leads to low activation of the RAF-MAPK pathway. Channel overexpression depolarizes the cell (Vm ≈ −10 mV), increasing the clustering of phosphatidylserine and K-Ras. This promotes RAF-MAPK signaling uncontrolled cell proliferation.