Defects in ion Channels. The Na + /K + Pump Na+/K+ Pump Direct active transport P-ATPase pump K in /...
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Transcript of Defects in ion Channels. The Na + /K + Pump Na+/K+ Pump Direct active transport P-ATPase pump K in /...
Defects in ion Channels
Defects in ion Channels
The Na+/K+ Pump
Na+/K+ PumpDirect active transportP-ATPase pump
Kin / Kout 35:1
Nain / Naout 0.08:1
Kin / Nain ~10:1
DirectionalityK inwardNa outwardThe ratio of Na+:K+ pumped is 3:2Tetrameric transmembrane proteinTwo alpha subunits (phosphorylated on S / T)Two beta subunits (glycosylated)Allosteric conformation E1 and E2
Against gradient
A Model Mechanism for the Na+/K+ Pump
Kin / Nain
Heart failure
The Na+/K+-ATPase pump
A Model Mechanism for the Na+/Glucose Symporter
Na+/Glucose Symporter
Indirect active transport-Intestinal epithelial cells-
Glucose, amino acids --low Conc. Outside the cellsNa+ --high Conc. Outside the cells
A. Two Na+ and One Glucose moleculesB. 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 Sin
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
Uncharged Solutes
Charged Solutes
Gin= +R T ln [S]in
[S]o
+zFVm
Gout= +R T ln [S]o
[S]in
-zFVm
Sz= ChargeF=Faraday constant
Vm= membrane potential
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 patch-clamp recording
electrode
Membrane potential [Vm]
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….)
How is this Electrical Signal generated?
Membrane potential=membrane voltage=transmembrane potential
is the difference in electrical potential (electric charge of ions) between the interior and the exterior of a cell.
Ionic Concentrations Inside and Outside Axons and Neurons
Development of the Equilibrium Membrane Potential
Electrochemical equilibrium: Chemical gradient and electrical potential are balanced
Equilibrium membrane potential: is the membrane potential in that electrochemical equilibrium.
RNA, proteins
Relative Concentrations of Potassium, Sodium, and Chloride Ions Across the Plasma Membrane of a Mammalian Neuron
Membrane potentialMore negative
Polarization
Membrane potentialMore positive
Depolarization=(Change the polarity of the membrane)
- // + - // +- // +
No net Movement
(more negative ?)Hyperpolarization
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 equilibriumMembrane 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
Ex Equilibrium membrane potential for X
X ion
z valence
Relationship between ion concentrations, membrane permeability & membrane potential
Vm = RT ln (PK)[K+]out + (PNa)[Na+]out + (PCl)[Cl-]in
(PK)[K+]in + (PNa)[Na+]in + (PCl)[Cl-]outF
Nernst equation – ion gradient and equilibrium membrane potential only permeable to that ion
Ex = RT ln [X]out
zF [X]in
Goldman equation
P=permeability
Electrical excitabilityAll 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 patch-clamp 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 tothe Channel)Acetylcholine
Mechano-gated(respond to mechanical forces)Hair cells of the inner ear -sound and motions
pA=picoampere
Conductance ~ ion permeability =1/Resistance
http://sites.sinauer.com/neuroscience5e/animations04.01.html
Ion channels-Structure
Voltage-gated
Voltage-gated potassium channels – multimeric4 subunits
Voltage-gated sodium channels –monomericfour 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 helices2 non-transmembrane -sheet
S4 – positively charged amino acidsvoltage 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
INACTIVE STATE
S4 subunits
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 S1-
S4 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 excitabilityAll 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+
Membrane trafficking= proteins and lipids movement
Signaling Transduction= proteins and lipids signaling
--ELECTRICAL( a few cells- neural and pancreatic cells-ions)
--NON-ELECTRICAL(most of them-2nd messenger)
The nervous system
Collects information
Processes information
Responses
Functions
Example:Traffic light
Figure 13-1 The Vertebrate Nervous System
PhotoreceptorsOlfactory
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 cortexCerebellum 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
Conduct signals
http://thebrain.mcgill.ca/flash/d/d_01/d_01_m/d_01_m_ana/d_01_m_ana.html#1
Nucleus,Golgi , ER, lysosomes
endosomes
?
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 mVb: Ion gradient and ion permeabilityc: pulse < 20 mV. --sub-threshold depolarizationd: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)
caused by 1-inward movement of Na+ and 2-outward movement of K+
Consequence: open and closing of voltage-gated Na+ and K+ Channels
+40 mV
-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 mVb: Ion gradient and ion permeabilityc: pulse < 20 mV. --sub-threshold depolarizationd:pulse > 20 mV. --Depolarization
The Passive Spread of Depolarization and Propagated Action Potentials in a Neuron
Passive depolarization= ~m
Propagated Action Potential= >mm
Number of Na+ channels
The Transmission of an Action Potential Along a Non-myelinated Axon
Propagated action potentialnerve 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 – oligodendrocytesPNS – Schwann cells
Initiation ? Termination ?
Conduct signals
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
1. Electrical
2.Chemical
Specialized membrane structures for cell-cell interaction / communication
Type Gap junction// Pre-/Post-synaptic regionsare in direct contact.
Type NON-Gap junction// Pre-/Post-synaptic regionsare 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- intracellularCa2+ 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
True for all neurotransmitters, except acetylcholine (Acetylcholinesterase – synaptic cleft)
Neurotransmitter use and recycling1. Re-uptake2. Degradation
Compensatory endocytosis
Example:Tetanus toxin-spinal cord
Botulinum toxin-motor neuronsSnake venon
Curare-plant extract
The Acetylcholine Receptor
Muscle cellsLigand-gated cation channel
Where are these receptors localized?Pre or postsynaptic membrane.
The Acetylcholine Receptor
Muscle cellsLigand-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)
Smart Drugs & Nutrients:How to Improve Your Memory and Increase Your Intelligence Using the Latest Discoveries In Neuroscience
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Phenytoin (Dilantin) (Epamin) Dilantin is known to most doctors and many other people as a treatment for epilepsy. However, it has a wide range of pharmacologic effects other than its anticonvulsant activity. There have been more than 8,000 papers published on Dilantin and there have been clinical reports of its usefulness in over 100 diseases and symptoms (Finkel, 1984).
Nerve signaling integration and processing
Neurotransmitters
Excitatoryexcitatory postsynaptic potential
Inhibitoryinhibitory postsynaptic potential
Nerve signaling integration and processing
Neurotransmitters
Excitatoryexcitatory postsynaptic potential
Threshold potential
Reach threshold by rapid firing of action potentialsand by signals received at multiple synapses
Integration of Synaptic Inputs
How is this Electrical Signal generated?
Sensory Receptor
Mechanoreceptors for touchThermoreceptors for temperature changeNocireceptors for painElectromagneticreceptors for lightChemoreceptors for taste, smell and blood chemistry
http://www.blackwellpublishing.com/matthews/rhodopsin.htmlhttp://www.youtube.com/watch?v=mxnI3tsOdOI
11 cis retinal
All trans retinal(vitamin A)
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
A drug used to treat cancer has been shown to enhance long-term (LTP) memory and strengthen neural connections in the brain,
ELECTRICAL
NON-ELECTRICAL