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Defects in ion Channels
Defects in ion Channels
The Na+/K+ Pump
Na+/K+ Pump
Direct active transport
P-ATPase pump
K
/ Kout 35:1
Nain /
Na
in
K
out 0.08:1
/ Nain ~10:1
Directionality
K inward
Against gradient
Na outward
The ratio of Na+:K+ pumped is 3:2
Tetrameric transmembrane protein
Two alpha subunits (phosphorylated
on S / T)
Two beta subunits (glycosylated)
Allosteric conformation E1 and E2
in
A Model Mechanism for the Na+/K+ Pump
K
in
/ Nain
Heart failure
The Na+/K+-ATPase pump
A Model Mechanism for the Na+/Glucose
Symporter
Na+/Glucose Symporter
Indirect active transport
-Intestinal epithelial cellsGlucose, amino acids --low Conc.
Outside the cells
Na+ --high Conc. Outside the cells
A. Two Na+ and One Glucose
molecules
B. Two Na+ molecules are released.
*(Na/K pump)
C. One Glucose molecule are
released.
The Movement of Substances
Across Cell Membranes (16)
Cotransport: Coupling
Active Transport to Existing
Ion Gradients
– Gradients created by active
ion pumping store energy
that can be coupled to
other transport processes.
Secondary transport: the
use of energy stored in an
ionic gradient
Control of acid secretion in the stomach
bicarbonate
Calculation of ∆G for the Transport of
Charged and Uncharged Solutes
So
Charged Solutes
Sin
Gin= +R T ln [S]in +zFVm
[S]o
G=Go+R T ln [S]in
[S]o
At Equil. K’eq.=1 …. Go
Gin= +R T ln [S]in
[S]o
Gout= +R T ln [S]o
[S]in
Gout= +R T ln [S]o -zFVm
[S]in
Sz= Charge
F=Faraday constant
Vm= membrane potential
Uncharged Solutes
Calculation of ∆G for the Transport of Charged and
Uncharged Solutes
Comparison of Simple Diffusion, Facilitated Diffusion,
and Active Transport
The Movement of Substances
Across Cell Membranes (6)
• The Diffusion of Ions through Membranes
– Ions cross membranes through ion channels.
– Ion channels are selective and bidirectional,
allowing diffusion in the direction of the
electrochemical gradient.
– Superfamilies of ion channels have been
discovered by cloning analysis of protein
sequences, site directed mutagenesis, and
patch-clamping experiments.
Measuring ion conductance by patchclamp recording
electrode
Membrane potential [Vm]
Membrane potential=membrane voltage=transmembrane potential
1. Diffusion from high concentration to low
2. Electroneutrality
•
Positive ion for each negative ion. (Counterion)
3. Separated ions have tendency to move
toward each other
•
Potential or voltage (…e- current….)
is the difference in electrical potential (electric charge of ions) between the interior and the exterior of a cell
How is this Electrical Signal generated?
.
Ionic Concentrations Inside and Outside
Axons and Neurons
Development of the Equilibrium
Membrane Potential
RNA, proteins
Electrochemical equilibrium:
Chemical gradient and electrical potential are balanced
Equilibrium membrane potential: is the membrane potential in that
electrochemical equilibrium.
Relative Concentrations of Potassium, Sodium,
and Chloride Ions Across the Plasma Membrane
of a Mammalian Neuron
-
//
-
+
Membrane potential
More negative
Polarization
//
+
-
//
+
No net
Movement
Membrane potential (more negative ?)
More positive
Hyperpolarization
Depolarization=
(Change the polarity of the membrane)
Relative Concentrations of Potassium, Sodium, and Chloride Ions
Across the Plasma Membrane of a Mammalian Neuron
Depolarization=
(Change in the polarity of the membrane)
Steady-State Ion Movements
Electrochemical equilibrium
Membrane potential=?
Relationship between ion concentrations,
membrane permeability & membrane potential
Nernst equation – describes electrochemical equilibrium and
equilibrium membrane potential only permeable to that ion
Ex = RT ln [X]out
zF
[X]in
X ion
Ex Equilibrium membrane potential for X
z valence
Relationship between ion concentrations,
membrane permeability & membrane potential
Nernst equation – ion gradient and equilibrium membrane
potential only permeable to that ion
Ex = RT ln [X]out
zF
[X]in
Goldman equation
Vm = RT ln (PK)[K+]out + (PNa)[Na+]out + (PCl)[Cl-]in
F
(PK)[K+]in + (PNa)[Na+]in + (PCl)[Cl-]out
P=permeability
Electrical excitability
All cells have a resting membrane potential (-//+, membrane)
Depolarization  resting membrane potential (Liver cells)
Excitable cells  depolarized and propagate (neural, muscle and
pancreatic cells) action potential
Action potential ~~ influx (inward movement) of Na+
efflux (outward movement) of K+
Measuring ion conductance by patchclamp recording
electrode
Ion channels--Patch Clamping
Voltage-gated
(respond to change in Voltage)
Voltage-gated Na+ and
K+ channels
Ligand-gated
(respond to Ligand that binds to
the Channel)
Acetylcholine
pA=picoampere
Mechano-gated
(respond to mechanical forces)
Hair cells of the inner ear -sound
and motions
Conductance ~ ion permeability =1/Resistance
http://sites.sinauer.com/neuroscience5e/animations04.01.html
Ion channels-Structure
Voltage-gated
Voltage-gated potassium channels –
multimeric
4 subunits
Voltage-gated sodium channels –
monomeric
four domains
The Movement of Substances
Across Cell Membranes (7)
• The voltage-gated potassium channel (Kv)
contains six membrane-spanning helices.
– Both N and C termini are cytoplasmic.
– A single channel has 4 subunits arranged to create an
ion-conducting pore.
– Channel can be opened, closed, or inactivated.
– S4 transmembrane helix is voltage sensitive.
– Crystal structure of bacterial K channel shows that a
short amino acid domain selects K and no other ions.
The General Structure of Voltage-Gated
Ion Channels
6 transmembrane α helices
2 non-transmembrane -sheet
+
S4 – positively charged amino acids
voltage sensor
(responsive to change in potential)
_
The structure of a eukaryotic, voltage-gated
K+ channel
The Function of a Voltage-Gated Ion
Channel
ACTIVE STATE
S4 subunits
INACTIVE STATE
Conformational states of a voltage-gated K+
ion channel
The Movement of Substances
Across Cell Membranes (9)
• Eukaryotic Kv channels
– Once opened, more than 10 million K+ ions
can pass through per second.
– After the channel is open for a few
milliseconds, the movement of K+ ions is
“automatically” stopped by a process known
as inactivation.
– Can exist in three different states: open,
inactivated, and closed.
The Movement of Substances
Across Cell Membranes (8)
• Eukaryotic Kv channels
– Contain six membrane-associated helices
(S1-S6).
– Six helices can be grouped into two domains:
• Pore domain – permits the selective passage of
K+ ions.
• Voltage-sensing domain – consists of helices S1S4 that senses the voltage across the plasma
membrane.
4.8 Membrane Potentials and
Nerve Impulses (1)
– Membrane potentials have been measured in all
types of cells.
– Neurons are specialized cells for information
transmission using changes in membrane potentials.
• Dendrites receive incoming information.
• Cell body contains the nucleus and metabolic
center of the cell.
• The axon is a long extension for conducting
outgoing impulses.
• Most neurons are wrapped by myelin-sheath
Electrical excitability
All cells have a resting membrane potential (-//+, membrane)
Depolarization  resting membrane potential (Liver cells)
Excitable cells  depolarized and propagate (neural and
pancreatic cells) action potential
Action potential ~~ influx (inward movement) of Na+
efflux (outward movement) of K+
Signaling Transduction= proteins and lipids signaling
--ELECTRICAL
( a few cells- neural and
pancreatic cells-ions)
--NON-ELECTRICAL
(most of them-2nd messenger)
Membrane trafficking= proteins and lipids movement
The nervous system
Functions
Collects information
Processes information
Responses
Example:Traffic light
Figure 13-1 The Vertebrate Nervous
System
Photoreceptors
Olfactory
The nervous system
• Neurons
• Glial cells
The nervous system
• Neurons – send & receive electrical
signals
– Sensory neurons – detect stimuli
– Motor neurons – transmit signals from the
CNS to muscles or glands
– Interneurons – process signals received from
other neurons and relay information to other
parts of nervous system
The nervous system
http://www.carleton.ca/ics/courses/cgsc5001/img/06/neuron.jpg
Neuron Shapes
Cerebral cortex
Cerebellum
axonless
neural cells
The nervous system
• Glial cells
– Microglia – phagocytic cells
– Oligodendrocytes – myelin sheath around
CNS neurons
– Schwann cells – myelin sheath around
peripheral neurons
– Astrocytes - blood brain barrier
http://thebrain.mcgill.ca/flash/a/a_01/a_01_cl/a_01_cl_
ana/a_01_cl_ana_2a.jpg
The Structure of a Typical Motor Neuron
Receive signals
Nucleus,
Golgi , ER, lysosomes
endosomes
http://thebrain.mcgill.ca/flash/d/d_01/d_01_m/d_01_m_ana/d_01_m_ana.html#1
Conduct signals
?
The structure of a nerve cell
Membrane Potentials and Nerve
Impulses (2)
• The Resting Potential
– It is the membrane potential of a nerve or muscle cell,
subject to changes when activated.
– K+ gradients maintained by the Na+/K+-ATPase are
responsible for resting potential.
– Nernst equation used to calculate the voltage
equivalent of the concentration gradients for specific
ions.
– Negative resting membrane potential is near the
negative Nernst potential for K+ and far from the
positive Nernst potential for Na+.
Measuring a membrane’s resting potential
Membrane Potentials and Nerve
Impulses (3)
• The Action Potential (AP)
– When cells are stimulated, Na+ channels open,
causing membrane depolarization.
– When cells are stimulated, voltage-gated Na+
channels open, triggering the AP.
– Na+ channels are inactivated immediately following
an AP, producing a short refractory period when the
membrane cannot be stimulated.
– Excitable membranes exhibit all-or-none behavior.
Action potential
Human diseases= Channelopathies
Epilepsy (seizures, convulsions)
Ataxia (Muscular coordination, defect in K+ channels)
Diabetes (ATP-sensitive potassium channel)
Formation of an action potential
Formation of an action potential
The Action Potential of the Squid Axon
Giant Squid Axon (1 mm)
a: -60 mV
b: Ion gradient and ion permeability
c: pulse < 20 mV. --sub-threshold
depolarization
d:pulse > 20 mV. --Depolarization
Changes in Ion Channels and Currents in
the Membrane of a Squid Axon During an Action Potential
Action potential: short/brief depolarization
and repolarization of membranes (plasma)
+40 mV
caused by 1-inward movement of Na+ and
2-outward movement of K+
Consequence: open and closing of
voltage-gated Na+ and K+ Channels
-75 mV
Changes in Ion Channels and Currents in the Membrane of
a Squid Axon During an Action Potential
Both Na+ and K+ channels are not perfect=
They are leaking channels
Membrane Potentials and Nerve
Impulses (4)
• Propagation of Action Potentials as an
Impulse
– APs produce local membrane currents depolarizing
adjacent membrane regions of the membrane that
propagate as a nerve impulse.
– Speed Is of the Essence: Speed of neural impulse
depends on axon diameter and whether axon is
myelinated.
• Resistance to current flow decreases as diameter increases.
• Myelin sheaths cause saltatory conduction.
The Action Potential of the Squid Axon
Giant Squid Axon (1 mm)
a: -60 mV
b: Ion gradient and ion permeability
c: pulse < 20 mV. --sub-threshold
depolarization
d:pulse > 20 mV. --Depolarization
The Passive Spread of Depolarization and
Propagated Action Potentials in a Neuron
Passive depolarization= ~m
Number of Na+ channels
Propagated Action Potential= >mm
The Transmission of an Action Potential
Along a Non-myelinated Axon
Propagated action potential
nerve impulse
All or none event
Propagation of an impulse
The structure of a nerve cell
The Transmission of an Action Potential
Along a Myelinated Axon
Saltatory propagation
Propagation of an impulse
Myelination of Axons
CNS – oligodendrocytes
PNS – Schwann cells
Conduct signals
Initiation ?
Termination ?
Membrane Potentials and Nerve
Impulses (5)
• Neurotransmission: Jumping the Synaptic
Cell
– Presynaptic neurons communicate with
postsynaptic neurons at a specialized
junction, called the synapse, across a gap
(synaptic cleft).
– Chemicals (neurotransmitters) released
from the presynaptic cleft diffuse to receptors
on the postsynaptic cell.
Synapses
Specialized membrane structures for cell-cell interaction / communication
1. Electrical
Type Gap junction// Pre-/Post-synaptic regions
are in direct contact.
2.Chemical
Type NON-Gap junction// Pre-/Post-synaptic regions
are NOT in direct contact, but they are very close (20-50 nm).
An Electrical Synapse
Passive transmission== speed is critical==“heart”
Membrane Potentials and Nerve
Impulses (6)
• Neurotransmission: Jumping the Synaptic
Cleft
– Bound transmitter can depolarize (excite) or
hyperpolarize (inhibit) the postsynaptic cell.
– Transmitter action is terminated by reuptake
or enzymatic breakdown.
Neurotransmitter –small molecule
that binds to a receptor within the
membrane of a postsynaptic
neuron
The sequence of events during synaptic
transmission with acetylcholine as the
neurotransmitter
20 to 50 nm
Figure 13-20 The Structure and Synthesis
of Neurotransmitters
(A) Excitatory, depolarization, 0.1 msec,
Na+
(B) Generate molecules (messenger),
seconds
(C) Excitatory, K+/Na+, 0.1 msec
Figure 13-21 The Transmission of a
Signal Across a Synapse
How are the neurotransmitters released?
A. Action potential- depolarization- intracellular
Ca2+ release (voltage-gated Ca2+ channels).
B.Vesicles movement and fusion, following
neurotransmitters release.
C. Neurotransmitters and receptor interaction.
D. Depolarization/ Hyperpolarization.
How is this Electrical Signal generated?
Neurotransmitter recycling
Neurotransmitter use and recycling
1. Re-uptake
2. Degradation
Compensatory endocytosis
Example:
Tetanus toxin-spinal cord
Botulinum toxin-motor neurons
Snake venon
Curare-plant extract
True for all neurotransmitters, except acetylcholine
(Acetylcholinesterase – synaptic cleft)
The Acetylcholine Receptor
Muscle cells
Ligand-gated cation channel
Where are these receptors localized?
Pre or postsynaptic membrane.
The Acetylcholine Receptor
Muscle cells
Ligand-gated cation channel
Membrane Potentials and Nerve
Impulses (7)
• Actions of Drugs on Synapses
– Interference with the destruction or reuptake
of neurotransmitters can have dramatic
physiological and behavioral effects.
– Examples include: antidepressants,
marijuana, LSD, cocaine, etc
The GABA Receptor
GABA – γ-aminobutyric acid
Ligand-gated channel
chloride (Cl-) ions
inhibits depolarization (influx of Cl-)
of postsynaptic neurons
anxiety, panic, and the acute stress response.
Example:
Valium /Librium
(Diazepam)
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Vitamins |
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Nerve signaling integration and
processing
Neurotransmitters
Excitatory
excitatory postsynaptic potential
Inhibitory
inhibitory postsynaptic potential
Nerve signaling integration and
processing
Neurotransmitters
Excitatory
excitatory postsynaptic potential
Threshold potential
Reach threshold by rapid firing of action potentials
and by signals received at multiple synapses
Integration of Synaptic Inputs
How is this Electrical Signal generated?
Sensory Receptor
Mechanoreceptors for touch
Thermoreceptors for temperature change
Nocireceptors for pain
Electromagneticreceptors for light
Chemoreceptors for taste, smell and blood chemistry
11 cis retinal
All trans retinal
(vitamin A)
http://www.blackwellpublishing.com/matthews/rhodopsin.html
http://www.youtube.com/watch?v=mxnI3tsOdOI
Membrane Potentials and Nerve
Impulses (8)
• Synaptic Plasticity
– Synapses connecting neurons to their neighbors can
become strengthened over time by long term
potentiation (LTP).
– The NMDA receptor binds to the neurotransmitter
glutamate and opens an internal cation channel.
– Subsequent influx of Ca2+ ions triggers a cascade of
biochemical changes that lead to synaptic
strengthening.
– LTP inhibitors reduce the learning ability of laboratory
animals.
Synaptic plasticity
• Dynamic quality of synapses
• Important in learning
• Repeated stimulation of neurons over short
period of time – “strengthening (mental
power) of synapses”
• Long-term potentiation (level of neurotransmitter)
– Hours, days, weeks, years
– Na+ / K+ / Ca2+ / Mg2+ / neurotransmitter
Synaptic plasticity
• Studies in hippocampus – memory formation
• Important in learning
• Repeated stimulation of neurons over short period
of time – “strengthening of synapses”
• Long-term Potentiation (LTP)
• Long-term Depression (LTD)
• NMDA (N-methyl d-aspartate) receptor – binds
glutamate
– Ca++ influx into post-synaptic neuron
– Biochemical events leading to synaptic strengthening
Synaptic plasticity
ELECTRICAL
NON-ELECTRICAL
A drug used to treat cancer has been shown to enhance
long-term (LTP) memory and strengthen neural connections in the brain,