Defects in ion Channels. The Na + /K + Pump Na+/K+ Pump Direct active transport P-ATPase pump K in /...

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 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 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


• 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.


• 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


• 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

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


• 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


• 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”


• 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.


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


• 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

Other Cognitive EnhancersAcetyl L-Carnitine (ALC) | Caffeine | Centrophenoxine (Lucidril) | Choline & Lecithin | AL721 (Egg Lecithin) | DHEA | DMAE | Gerovital (GH 3) | Ginkgo Biloba: A Nootropic Herb? | Ginseng | Hydergine | Idebenone | Phenytoin (Dilantin) | Propranolol Hydrochloride (Inderal) | Thyroid Hormone | Vasopressin (Diapid) | Vincamine | Vitamins | Xanthinol Nicotinate

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


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)


• 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

Defects in ion Channels. The Na + /K + Pump Na+/K+ Pump Direct active transport P-ATPase pump K in /...

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