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Origins of Membrane Potential in Cells. Biophysics 702 Chen Gu. What is membrane potential ? Why is it important? How is membrane potential generated? How do we calculate membrane potential ? How does membrane potential encode signals? - PowerPoint PPT Presentation
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Origins of Membrane Potential in Cells
Biophysics 702
Chen Gu
What is membrane potential? Why is it important?
How is membrane potential generated?
How do we calculate membrane potential?
How does membrane potential encode signals?
What are the carriers for membrane potentials?
Vin
Vout = 0
The membrane potential (Vm) is defined as
Vm = Vin – Vout
intracellular
extracellular
Resting membrane potential -60 to –70 mV for neuronsDepolarization become more positive Hyperpolarization become more negative
What is membrane potential? Why is it important?
How is membrane potential generated?
How do we calculate membrane potential?
How does membrane potential encode signals?
What are the carriers for membrane potential?
The membrane potential results from a separation of positive and negative charges across the cell membrane
Electrical and thermodynamic forcesdetermine the passive distributionof ions
R
I
V
I = V/R
’s LAW
P
Q.
R
Q = P/R
.
C1 C2
C
R
J
J = C/R
C1+
V
R
I
++
+
+
+ +
+ +
+
++
+
C2+
I = C/R
Diffusiondown
Chemical Gradient
Diffusion down
Electrical Gradient
Concept of an Equilibrium Potential for an ionic species:
The potential at which the movement of ions across the membrane is in electrochemical equilibrium, i.e. the voltage necessary to result in no net movement of the ionic species across the membrane.
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
-90 mV
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
+55 mV
Out of Equilibrium In Equilibrium
Maintaining the resting membrane potentialMaintaining the resting membrane potential
K
K
KK
KK
K
K
KK K
K
K
K
K
K
+++++++++
Concentration gradient
voltage gradient
---------
Intracellular Extracellular
-102 mV
EK
Ne
ga
tive
to
EK
Po
sitiv
e t
o E
K
gK
K+ moves into cell
gKK+ moves out of cell
Reversal potential(No net movement of K+)
Time
Normalcurrent injection
Voltage response
gK
Increased gK
K+ moves out of cell
K+ moves into cell
EK
-102
Time
What is membrane potential? Why is it important?
How is membrane potential generated?
How do we calculate membrane potential?
How does membrane potential encode signals?
What are the carriers for membrane potential?
Resting membrane potentialsResting membrane potentials
Nernst equations for biological ions:Nernst equations for biological ions:
extracellular
intracellular
ENa = +56Na+ (150)
EK = -102K+ (3)
ECl = -76Cl- (120)
ECl = +125Ca2+ (1.2)
Na+ (18) K+ (135) Cl- (7) Ca2+ (0.1 µM)Na+,K+-ATPase
-60 to -75 mVNSCC
Ek = lnRTF
[K]o
[K]i
ENa = lnRTF
[Na]o
[Na]i
ECa = lnRT2F
[Ca]o
[Ca]i
ECl = lnRT-F
[Cl]o
[Cl]i
Anions: Cl- and proteinsCations: K+ diffusion potential Na+ diffusion potential
Ca2+ diffusion potentialNa+/K+-ATPase
Important: Ionic concentration differences across cell membranes determines the membrane potential
The concentration differences of ions are due to the biophysics of the channels and pumps
Guyton, Textbook of Physiology
E (ion) = RT/zF ln ([ion]outside/[ion]inside)
Nernst Equation
Na+Na+ Na+
Na+Na+
Na+ Na+
Na+
Na+
@ 370 C RT/F= (27/z) Convert to log 2.3 x 27/z = 63
@ 0o C = 54@ 24oC = 59@ 37oC = 63
E (ion) = 63 log ([ion]outside/[ion]inside)
The “Voltage Diagram”
-90 Vr (i.e. resting Vm)
ENa+ = 63 log [ ]o/[ ]i142 10 = +73 mv
ECl- = 63 log [ ]o/[ ]i 103 4 = 89 mv
-1
-
EK+ = 63 log [ ]o/[ ]i
Vm
Mem
bran
e V
olt a
ge o
r P
oten
t ial (
mV
)
Time
0
4 140 = -97 mv
+72 ENa+
Ecl--89
-97 EK+
The “Voltage Diagram”
+
-90 Vr (i.e. resting Vm)
-97 EK+ (Equilibrium Potential for K+)
+72 ENa+ (Equilibrium Potential for Na+)
Vm
Mem
bran
e V
olt a
ge o
r P
oten
t ial (
mV
)
Time
0---
-
+++
ECl- (Equilibrium Potential for Cl- )-89
Maintaining the resting membrane potentialMaintaining the resting membrane potential
Vm = lnRTF
pK[K+]o + pNa[Na+]o + pCl[Cl-]i
pK[K+]i + pNa[Na+]i + pCl[Cl-]o
The Goldman-Hodgkin-Katz Equation:The steady state membrane potential for a given set of ionic concentrations inside and outside the cell and the relative permeability of the membrane to each ion
extracellular
intracellular
ENa = +56Na+ (150)
EK = -102K+ (3)
ECl = -76Cl- (120)
ECl = +125Ca2+ (1.2)
Na+ (18) K+ (135) Cl- (7) Ca2+ (0.1 µM)Na+,K+-ATPase
-60 to -75 mVNSCC
Lipid Bilayer
Anion-
Anion-
Anion-Anion-
Anion-
Anion-
3 Na+
2 K+
ATPase
(1)Three Primary reasons for a net negative potential across the membrane
(2)
EXTRACELLULAR SPACE
INTRACELLULAR SPACE
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
K+
Na+
Electrongenic Na/K ATPase High IC [Anions]
(3) Relative Permeabilities of
dominant cations
Changes in membrane potential due to ion movementChanges in membrane potential due to ion movement
Depolarization:
Initiators: Na+ channels nonselective cation channels
(NSCC) Na+,K+-ATPase
Terminators: K+ channels Cl- channels
extracellular
intracellular
ENa = +56Na+ (150)
EK = -102K+ (3)
ECl = -76Cl- (120)
ECl = +125Ca2+ (1.2)
Na+ (18) K+ (135) Cl- (7) Ca2+ (0.1 µM)Na+,K+-ATPase
-60 to -75 mVNSCC
What is membrane potential? Why is it important?
How is membrane potential formed?
How do we calculate membrane potential?
How does membrane potential encode signals?
What are the carriers for membrane potential?
Types of electrical signalsTypes of electrical signals
• Graded potentials: Variable-strength signals that lose strength as they travel through the cell.
a. Can be depolarizations (Na+ channel) or hyperpolarizations (K+ or Cl- channel)b. Begins on the cell membrane at the point where ions enter from the extracellular
fluid (local current or electrotonic current)c. The strength or amplitude is directly proportional to and is determined by the
number of charges that enter the cell, which in turn is determined by the number of receptors which are opened. (concentration of the neurotransmitters and density of the receptors)
d. The size of the graded potential decreases as it spreads out from its point of origine. Graded potentials travel through the neurons until they reach the trigger zone, the
point where an action potential is generated. Depending on the strength of the graded potential, it either triggers an action potential or dies out (threshold potential).
f. Can be summed: spatial summation and temporal summation
• Action potentials: Signals that travel for long distances through the neuron without losing strength.
a. Rapid electrical signals that pass along the axon to the axon terminal.b. Identical to each other and do not diminish in strength when traveling through the
cellc. The strength of the graded potential that initiates an action potential has no
influence on the action potential as long as it is above threshold.d. All-or-none
Comparison of graded potential and action potentialComparison of graded potential and action potentialFeature Graded Potential Action Potential
Type of signal Input signal Conduction signal
Where it occurs Usually dendrites and cell body. Axon hillock, initial segment and entire length of axon
Types of gated ion channels Mechanically or chemically gated channels
Voltage-gate channels
Ions involved Usually Na+, K+, and Cl- Na+ and K+
Type of signal Depolarizing (Na+ ) or hyperpolarizing (K+, Cl- )
Depolarizing
Strength of signal Depends on initial stimulus; can be summed
Is always the same as long as graded potential is above threshold; cannot be summed
What initiates the signal Entry of ions through chemically or mechanically gated ion channels
Above-threshold graded potential arrives at the integration zone
Unique characteristics No minimum level required to initiate a graded potential Two signals coming close together in time will sum
Threshold stimulus required to initiate action potential Refractory period: two signals too close together in time cannot sum Initial stimulus strength is indicated by frequency of a series of action potentials
What is membrane potential? Why is it important?
How is membrane potential formed?
How do we calculate membrane potential?
How does membrane potential encode signals?
What are the carriers for membrane potentials?
Voltage-gated ion channels: currentsVoltage-gated ion channels: currents
INa,t
ICa,L
ICa,N
ICa,T
-100
-10
Na+
Ca2+
Voltage (mV)
INa,p
-100
-10
K+
Voltage (mV)
IK
IC
IA
IM
-100
-10
Na+/K+
Voltage (mV)
Ih
Inward currents Outward currents
Voltage-gated ion channels: structureVoltage-gated ion channels: structure
Perez-Reyes, Cell Mol Life Sci 56, 660-669, 1999
The structure of mammalian Kv1.2/Kv2
Long et al, 2005 Science
Voltage-gated ion channels: the superfamily Voltage-gated ion channels: the superfamily
Yu et al., Pharmacol Rev 57: 387-395, 2005
Voltage-gated ion channels: structure of CaVoltage-gated ion channels: structure of Ca2+2+ channels channels
s
Bers and Perez-Reyes, Cardiovasc. Res. 42, 339-360, 1999
Skeletal muscle L-type Cardiac muscle L-type
Ligand-gated ion channels (ionotropic receptors)Ligand-gated ion channels (ionotropic receptors)
. .. .
..
...
.
ligand
ions
Bind to neurotransmittersReceptor channelsMediate fast synaptic transmission
Presynaptic terminal
IP3
ICa
mGluR1
AMPARCa2+
Ca2+Gq/11
PLC
4
DAGCa2+
Postsynaptic terminal
1BNMDAR
5 mV20 ms
ionotropic glutamate receptorsionotropic glutamate receptors
Mg2+
TM4
NR1
TM4NR2
TM4
NR1
TM4NR2
NR2NR1
NR2
TM1
TM4
TM2TM3
NR1NH2
COOH
extracellular
intracellular
NH2
COOH
TM1 TM2 TM3TM4
NMDA: NMDA: N-methyl-D-aspartateCoincidence detector because of voltage dependent
Mg2+ block
GluR1
NR1
GluR2GluR3GluR4
GluR5GluR6GluR7
NR2ANR2B
NR2CNR2D
KA1KA2
10%AMPA: AMPA: -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid
kainatekainate
TM1TM3
TM1
TM3
TM1 TM3
TM1
TM3
Cys-loop superfamilyCys-loop superfamily
TM2TM1
TM3TM4
TM2
TM1
TM3
TM4
TM2
TM1
TM3
TM4TM2
TM1TM3
TM4
TM2
TM1
TM3
TM4
TM1
TM4TM2
TM3
NH2
COOH
extracellular
intracellular
NH2
COOH
TM1 TM2 TM3 TM4
Cation channelsCation channelsNicotinic acetylcholine receptorNicotinic acetylcholine receptor
I, epithelial 9; II, neuronal 7,8; III, neuronal 2–6 and 2–4
III-1: 2,3,4,6; III-2, 2,4 III-3, 5, 3;
IV, muscle 1, 1, , , and IV-1, 1IV-2, , , IV-3, 1.
5-HT3 serotonin receptor5-HT3 serotonin receptor5-HT3A, 5-HT3B
Anion channelsAnion channelsGABAGABAAA receptor receptor
Glycine receptorGlycine receptor
Muscle-type
homo-oligomeric 7
hetero-oligomeric 42
Neuronal type
Corringer et al., Annu. Rev. Pharmacol. Toxicol. 40:431-458, 2000
subf
amili
es
P2X receptorsP2X receptors
P2X2
P2X3
P2X5
P2X4
P2X1
P2X6
P2X7
b
Plasma membrane
a
C tail length varies
Cysteine richextracellular
loop
Each channel may contain three to six subunits
• Activated by ATP• Cation nonselective• ~6.5% of current is carried by Ca2+
Khakh et al., Pharmacol. Rev. 53, 107-118. 2001
NH2
Anion channelsAnion channels
GABAA receptor
CLCClC-5
Text books:
Chapter 6Fundamental Neuroscience
Chapter 7Principles of Neural Science