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General Features of Ion Channels

-->Represent **INTEGRAL PROTEINS** that embedd & span the width of the entire membrane
-->3 Major Types:
1)Ungated Channels
2)Voltage Gated Channels
3) Ligand Gated Channels

Ungated Channels

-->Channels which are ALWAYS OPEN for a specific ion
-->Do not contain a V(max)
-->Ex. Potassium through K+ Channels

Voltage-Gated Channels

-->Channels that are sensitive to MEMBRANE VOLTAGE
-->Ex. Voltage-Gated Na+ channels during an AP in skeletal muscle / nerves
***NOTE: K+ channels can be voltage-gated as well

Ligand-Gated Channels

-->Channels which open or close when a LIGAND binds to them
-->The substance that binds the channel is normally NOT the solute to be transported inside the cell
-->Ex. Nicotininc acetylcholine receptor protein on the motor end plate

Diffusion Potential

-->Is the potential difference generated across a membrane when a CHARGED SOLUTE (i.e. an ion) diffuses down its concentration gradient
-->A diffusion potential can only be generated IF the membrane is PERMEABLE to that ion
-->Is dependant on 2 requirements:
1)Concentration Gradient (The size of the driving force
2)Selective Permeability of the membrane (membrane MUST be permeable to the ion)

2 Factors Used to evaluate diffusion & equilibrium potentials

1)Chemical Force (Depends on the concentration gradient of the ion)
2)Electrical Force (Depends on the attraction of the ion to the charge on the interior of the membrane AFTER the molecule has diffused down it's concentration gradient)
***NOTE: Diffusion & Equilibrium Potential DO NOT ASSUME THAT THE INSIDE OF THE CELL MAINTAINS A NEGATIVE CHARGE AT ITS RESTING MEMBRANE POTENTIAL

**If you see a question asking to calculate the Net Force of an ion**

-->Take the absolute difference in voltage

The relative concentrations of the major electrolytes in the intracellular & extracellular spaces

(1) For Na+:
[ C(o) ] = 140 mEq/L
[ C(i) ] = 10 mEq/L
(2) For K+:
[ C(o) ] = 4 mEq/L
[ C(i)] = 120 mEq/L
(3) For Cl-
[ C(o) ] = 100 Eq/L
[ C(i) ] = 4 mEq/L
(4)For Ca2+
[ C(o) ] = 3 mEq/L
[ C(i) ] = 1 x 10^-4 µM

Rate of Diffusion of an ion ("Chord Conductance Eq.)

-->Depends on 2 characteristics:
1)Membrane Conductance to that ion [ g(ion) ]
2)Net Force on an ion (v - e(x) ); v = membrane potential; e(x) chemical driving force on ion x
(***NOTE: For Net force of ion, you can just take the absolute difference of the 2 voltages)
***For problems, the formula is NOT necessarily to know

Evaluation of Strength of a current in a net force problem

1)If the current is 10-30mV --> SMALL CURRENT
2)If the current in 30-50mV ->MEDIUM CURRENT
3)If the current is >50mV --> LARGE CURRENT

Equilibrium Potential

-->The diffusion potential that exactly balances or opposes the tendency for diffusion down the concentration difference
-->Creates an ELECTROCHEMICAL EQ., where the electrical & chemical forces acting on the ion are EQUAL & OPPOSITE
1)Net movement of the ion is ZERO
2)The potential at the pint can be calculated by the NERNST EQ. [ Expressed as E(ion) ]

Typical Values for Equilibrium Potentials

1) E(Na+) = +65mV
2)E(K+) = -85mV
3)E(Cl-) = -90mV
4)E(Ca2+) = +120mV

Features of Normal Concentrations of K+ in the ECF vs. states of hyperkalemia & hypokalemia

**SEE FORMULA SHEET FOR DETAILS**

Features of Resting Membrane Potential (RMP)

-->Is the resting membrane potential that exist acroos the cell membrane at REST
-->Each permanent ion attempts to drive the membrane potential toward its own equilibrium potential
1)Ions with the GREATEST permeabilities or conductances AT REST will make the greatest contribution to the resting membrane potential
-->Expressed in millvolts (mV)
-->The RMP in excitable cells falls in the range of **-70 to -90mV** (-70mV is typically taken)
1) The resting membrane potential is CLOSE to the eq. potentials for **K+ and Cl-** b/c the permeability to these ions AT REST is high (visa versa for Na+ & Cl-)

Which channels are responsible for causing the RMP?

-->Ungated K+ channels ("K+ leak channels")
-->**Na+/K+ ATPase Pump** creates the gradient for K+ leak channels to pump K+ out of the cell, which creates the -70 to -90mV RMP inside the cell
-->**Don't forget that CARDIAC GLYCOSIDES (*DIGITALIS/OAUBAIN**) can inhibit Na+-K+ ATPase (resulting in an incr. in the [C(i)] of Na+ and a decr. in [C(i)] of K+)

**SEE SAMPLE PROBLEMS RELATED TO GRAPHS & RMP's of K+ & Na** in powerpoint

**Don't forget that only K+ & Cl- contribute the MOST to the RMP** (Na+ & Ca2+ will NOT have any appreciable affect on the RMP)

Features of an action potential

-->Defines any phenomenon of rapid depolarization followed by repolariztion fo the membrane potential, over the course of a few milliseconds (ms) to as long as 200 ms
-->AP's propagate along the surface of EXCITABLE CELLS ONLY (i.e. cells that can produce an AP)
-->Represents the principal means of transmitting information in the nervous system
-->Used in contraction of skeletal & cardiac muscle
-->To generate an AP, the membrane potential must be taken to a THRESHOLD POTENTIAL (-55mV)

Terminology of Action Potentials

Polarization:
-->The resting membrane potential is polarized, which simply means that the outside and inside of a cell have a different net charge.
-->The normal cell has a more negative charge on the interior of the cell (i.e. -70 mV).

Depolarization:
-->The change in membrane potential closer to 0 mV (completely depolarized).

Threshold:
-->For an electrically excitable cell, the potential at which voltage-gated ion channels first open

Overshoot:
-->The temporary reversal of the membrane potential polarity (i.e. that is, when the inside of a cell becomes positive relative to the outside.

Repolarization:
-->The return of a depolarized or overshot membrane potential towards its resting membrane potential.

Hyperpolarization:
-->The membrane is hyperpolarized when the potential is more negative than the resting level.

7 Detailed Steps of the Action Potential

1)Resting State
2)Sub-Threshold Depolarization (-70mV to -55mV)
3)Action Potential (-55mV to 0mV)
4)Overshoot (0mV to +35mV)
5)Repolarization
6)Hyperpolarization
7)Return to Resting Membrane Potential

Features of Resting State

-->Membrane potential is kept at the resting level, which is close to the Eq. potential of K+ b/c there are MORE open K+ channels (K+ leak channels) than Na+ channells
-->Both voltage-gated Na+ & K+ channels are closed

Features of Sub-Threshold Depolariztion

-->Region where the membrane potential is REDUCED from resting potential closer to threshold level
-->The voltage-gated Na+ channels are still CLOSED, but it is the **LIGAND-GATED channels & **passive ion movement that is responsible for creating these GRADED potentials

Graded Potentials

-->Changes in the membrane potential that are confined to a relatively SMALL region of the plasma membrane
-->Occur in varying degrees of STRENGTH & MAGNITUDE

Features of Depolarization (Upstroe)

-->When the membrane potential reaches the THRESHOLD POTENTIAL, there is a rapid opening of voltage-gated Na+ channels, where:
1)Na+ enters the cell to cause depolariztion phase of the action potential
2)Depolarization initiates the opening of MORE voltage-gated Na+ channels (" + feedback loop")
-->Membrane potential goes TOWARD Eq.(Na+), but DOES NOT ever reach its value
NOTE: ***The K+ channel's gate remains CLOSED during this period

Features of Overshoot

-->Occurs when the Na+ permeability reaches its PEAK VALUE
-->Represents the part of the AP that lies ABOVE 0 mV

Features of Repolarization

-->Refers to the abrupt decline of the Na+ permeability as the membrane potential reaches its peak value, due to ***2 factors:
1)***Closure of the INACTIVATION GATE causes the closure of the voltage-gated Na+ channels (Leading to stoppage of inward Na+ current)
2)The DEPOLARIZED STATE of the membrane causes the **opening of voltage-gated K+ channels (*Slow to open, and Slow to close**)

Features of Hyperpolarization

-->Occurs when the membrane potential becomes MORE NEGATIVE than the resting potential, due to:
1)***Increased K+ permeability
2)SLOW CLOSURE of voltage-gated K+ channels
-->Changes in the ion channels as the cell becomes more hyperpolarized:
1)The Inactivation Gate of the Na+ channel (near cell interior) OPENS
2)The Activation Gate of the Na+ channel (near cell exterior)
3)The K+ channels close
CLOSES

Features of Return to resting potential

-->***The state where BOTH the Na+ & K+ channels have returned to their RESTING STATES, where:
1)The Na+/K+ ATPase pump RESTORES Na+ & K+ ions back to their proper side of the membranes
-->Once ALL of the ions are back at their ORIGINAL CONCENTRATIONS, the hyperpolarization ENDS & the membrane is back at rest again

States of the Gates of the Voltage-Gated Na+ Channels

1)At REST (membrane interior is neg.; AT REST):
-->Activation Gate is CLOSED
-->Inactivation Gate is OPEN
2)During Depolarization (membrane interior is positive)
-->Activation Gate is OPEN
-->Inactivation Gate is OPEN
3)During Repolarization
-->Activation Gate is CLOSED
-->Inactivation Gate is OPEN

Importance of **TETRODOXIN & LIDOCAINE**

-->TETRODOXIN is a toxin from the Japanese PUFFER FISH
1)**Blocks voltage-gated Na+ channels *IRREVERSIBLY**, which explains why the symptoms are so severs (Ex. muscle weakness, respiratory failure, & incr. chance of DEATH)
-->LIDOCAINE is LOCAL ANESTHETIC
1)**SHORT-ACTING**; blocks the transmission of pain impulses
2)Considered a REVERSIBLE anesthetic b/c its affect can be
-->Both of these mol. BLOCK the ***Voltage-Gated Na+ Channels, which prevent the occurrence of the NERVE ACTION POTENTIAL

Time Course of Voltage & Conductance Changes During a Nerve Action Potential (See Post-It for Example Questions on diff. regions of ionic conductance

Features of the all or none response of an action potential

-->Contains 2 major features:
(1)"All" Component: Once the THRESHOLD is reached, an AP of the **SAME SIZE**, regardless of the strength of the stimulus
(2)"None" Response: A Weak Stimulus WILL NOT produce an AP b/c the membrane potential DOES NOT REACH MEMBRANE POTENTIAL

Features of a Refractory Period

-->***The period during which a second AP CANNOT be elicited with a threshold stiumulus
-->Is composed of 2 parts:
1)Absolute Refractory Period
2)Relative Refractory Period

The Absolute Refractory Period (ARP)

-->Represents the period during which another AP cannot be ELICITED, no longer HOW STRONG THE STIMULUS b/c:
1)***100% of the voltage-gated Na+ channels are either ALREADY OPEN or are in the INACTIVATED STATE
-->Covers the period from the **resting membrane potential (RMP) up to *the first 1/3rd of repolarization**
**IMPORTANT**ARP occurs due to the closure of the INACTIVATION (Inner) GATES of Na2+

The Relative Refractory Period (RRP)

-->Refers to the period where a second AP can occur, but only with a LARGER-THAN-THRESHOLD STIMULUS b/c:
1)A STRONGER inward Na+ current is required to reach the threshold from the HYPERPOLARIZED STATE of RMP
-->Covers the region from **1/3rd of the repolarization phase* to the *end of repolarization phase**

ARP & its relationship to TETANY (**Not TETANUS**)

-->Tetany refers to the IVOLUNTARY CONTRACTION of skeletal muscle, that often occurs when the EXTRACELLULAR Ca2+ levels fall (~40% of its normal value)
-->Low extracellular calcium ***INCR. THE OPENING of Na+ channels in excitable membranes, which leads to:
1)The membrane depolarization
2)Spontaenous firing of ACTION POTENTIALS
-->**HOWEVER**, if the cell is at ARP, then membrane WILL NOT depolarize, & TETANY will not occur

RRP & its relationship to the contractions of the heart

-->Action potentials in cardiac muscle are VERY LONG in duration (> 200 msec) b/c:
1)Cytoplasmic Ca2+ remains elevated longer, so that the CONTRACTION remains longer
-->During membrane repolarization during the RRP, the CONTRACTION is decr. in strength, making it DIFFICULT to initiate another AP during the repolarization period
1)Therefore, one contraction CANNOT build/summate on the next contraction
-->***This is physiologically important b/c it means that every contraction period ("Systole") will be accompanied by a resting period ("Diastole") in order for the heart can refill with blood

Features of Propagation of an AP in a myelinated axon

(1)Myelin
-->Formed by SCHWANN CELLs in the PNS & OLIGIODENDROCYTES in the CNS
-->Provide the axon segment insulation where no ion movement can occur
-->The VELOCITY of an AP propagation is much FASTER along myelinated axon
(2)Nodes of Ranvier
-->Represent bare segments of the axonal membrane with a HIGH density of of **voltage-gated Na+ channels**
(3)Saltadory Conduction
-->Describes the ability of the AP to jump from node to node

Conduction Velocity (CV)

-->Refers to the speed of the progation of an action potential
-->Depends on 2 factors:
1)Diameter of the nerve fiber(d) (***The larger the diameter, the faster the conduction)
2)Myelination of the nerve fiber (***The higher amt of myelin (m) surrounding the axon)
NOTE: alpha-motor fibers provide the fastest conduction, & c-fibers represent the slowest form of conduction

Clinical Significance of Myelin

1)Mutilple Sclerosis
2)Guillian Barre Syndrome
-->Both syndromes will present with severe disturbances in MOTOR & SECONDARY FXN's b/c of the slowed conduction

Multiple Sclerosis

-->A Demyelinating disease of the CNS
-->Loss of the myelin sheath leads to the following clinical features that indicate an overall ***LACK IN COORDINATION:
1)Muscle weakness
2)Vision problems (Ex. Blurred vision)
3)Speech problems

Guillian Barre Syndrome

-->A Demyelinating disease of the PNS
-->***Often associated with a VIRAL INFECTION 2-3 weeks prior to the onset of symptoms
-->Patients often present with:
1)***Progressive ascending paralysis (from lower to upper limbs)
2)Deep tendon reflexes are LOST
3)May affect face, trunk, & diaphram

Different Ways in which the generation of an AP can be affected

(1)Blockage of Na+ sensitive channels
-->Ex. **Lidocaine (Local Anesthetic), **Tetrodotoxin (From Jap. puffer fish(
(2)Persistent depolarization of the membrane
-->Ex. ***Hyperkalemia (Decr. in concentration gradient of K+, which decr. amout of K+ efflux, leading to a depolarized state that stimulates the premature closure of the inactivation gate of the Na+ channels)

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