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System of the Organ
The Nervous System
2
LIU Chuan Yong
刘传勇
Department of Physiology
Medical School of SDU
Tel 88381175 (lab)
88382098 (office)
Email: [email protected]
Website: www.physiology.sdu.edu.cn
Characteristics of the Course
• Integration (整合)– From basic to clinical
• Combine with PBL, Laboratory and Clinical Clerkship
• In Bilingual (in English and Chinese)
Chapter 2
Elements of Cellular and Molecular Neuroscience
Neurones and Glial Cells
Review
Sections I
Neurone Excitability
Neuron Excitability
• Part 1 Facilitated Diffusion through Channel
• Part 2 Resting Membrane Potential
• Part 3 Action Potentials
• Part 4 Nerve Conduction
• Part 5 Synaptic Transmission
Part I Facilitated Diffusion through Channel
• Voltage gated channel
• Chemically gated channel
• Mechanically gated channel
Categories of Transport Across the Plasma Membrane
Cell membrane is selectively permeable to some molecules and ions.
Mechanisms to transport molecules and ions through the cell membrane:Non-carrier mediated transport.
Simple Diffusion (单纯扩散) :O2, CO2, steroids, H2O
Facilitated Diffusion (易化扩散) :Via Carrier: glucose, amino acidChannel
Voltage, Chemical and Mechanical gating channel
Active Transport 主动转运Primary active transportSecondary active transport
Facilitated diffusion through channels
Definition transport proteins complex
have watery spaces all the way through the molecule
allow free movement of certain ions or molecules.
channel proteins. Channel mediated diffusion.
Basic Structure of Voltage-Gated Calcium Channels
Cain & Snutch,2010
The alpha subunit is responsible for basic electrophysiological and pharmacological properties
The auxiliary subunits have regulatory roles
Principal one alpha subunit and several auxiliary subunits
Characteristics of the channels:
selectively permeable to specific substances (irons)
opened or closed by gates
Facilitated diffusion through channels
Classification of the channels (according to the gating mechanism):
Voltage gated channel
Chemically gated channel
Mechanically gated channel
Voltage-gated Channel
The molecular conformation of the gate responds to the electrical potential across the cell membrane
Voltage-gated (or dependent) channel.
Voltage-gated Na+ Channels Many flavors
nerves, glia, heart, skeletal muscle
Primary role:
action potential initiation
Multi-subunit channels (~300 kDa)
Skeletal Na+ Channel: 1 (260 kDa) and 1 (36kDa)
Nerve Na+ Channel: 112 (33 kDa)
gating/permeation machinery in 1 subunits
Three types of conformational states (close,
open or activation, inactivation) - each
controlled by membrane voltage
CO2H
Outside
NH2
+++
+++
+++
+++
Inside
Na+ Channel -Subunit Structure
I II III IV
RVIRLARIGRILRLIKGAKGIR+ + + + + + + +
IFM
IFM
- Inactivation “Gate” IVS4 Voltage Sensor
NH2
CO
2 H
I 异亮氨酸; F 苯丙氨酸; M 甲硫氨酸
Mechanism of voltage-gated ion channels work
movement of the voltage sensor generates a gating current
S4 transmembrane segment may be voltage sensor
pore formed by a nonhelical region between helix 5 and 6 (postulated to form sheets)
inactivation gate is in the cytoplasm
Molecular structure
• A large α subunits of 260 kDa and smaller βsubunits of 30–40 kDa
Tetrodotoxin (TTX ,河豚毒 ) selectively block the voltage-gated Na+ channel
Na+ Channel Conformations
Conductingconformation
Non-conductingconformation(s)
(at negative potentials)(shortly after more depolarized potentials)
Another Non-conductingconformation
(a while after moredepolarized potentials)
IFM IFM
IFM
Closed Open InactivatedOutside
Inside
Chemically-Gated Ion Channel
Some protein channel gates are opened by the binding of another molecule with the protein
causes a conformational change in the protein molecule that opens or closes the gate.
chemical gating.
chemically-gated (or dependent) channel
Ligand 配体 -Operated ACh (乙酰胆碱) Channels
Ion channel runs through receptor. Receptor has 5
polypeptide subunits that enclose ion channel.
2 subunits contain ACh binding sites.
Ligand-Operated ACh Channels
Channel opens when both sites bind to ACh.Permits diffusion of Na+
into and K+ out of postsynaptic cell.
Inward flow of Na+ dominates .Produces EPSPs.
Ligand-Operated ACh Channels
Mechanically-gated channel
Some protein channel gates may be opened by the mechanical deformation of the cell membrane. mechanically-gated channel.
It plays a very important role in the genesis of excitation of the hair cells
Organ of Corti
When sound waves move the basilar membrane it moves the hair cells that are connected to it,
but the tips of the hair cells are connected to the tectorial membrane the hair cell get bent .
There are little mechanical gates on each hair cell that open when they are bent.
K+ goes into the cell and Depolarizes the hair cell. (concentration of K+ in the endolymph is very high)
Water Channel
The structure of aquaporin
(AQP)
Part 2 Membrane Resting Potential
A constant potential difference across the resting cell membrane
Enable the cell ability to fire an action potential (动作电位)
Determine the basic signaling properties of neurons
Membrane Resting Potential
The membrane potential results from a separation of positive and negative charges across the cell membrane.
Membrane Resting Potential
excess of positive charges outside and negative charges inside the membrane
maintained because the lipid bilayer acts as a barrier to the diffusion of ions
an electrical potential difference
ranges from about 60 to 70 mV
Potentiometer
Concept of Resting Potential (RP)
A potential difference across the cell membrane at the rest stage or when the cell is not stimulated.
Property: constant or stable negative inside relative to the outside different in different cells.
Ion Channels
Two Types of Ion Channels
Gated
Non-Gated
Resting Membrane Potential
Na+ and Cl- are more concentrated outside the cell
K+ and organic anions (organic acids and proteins) are more concentrated inside.
Intracellular vs extracellular ion concentrations
Ion Intracellular Extracellular
Na+ 5-15 mM 145 mMK+ 140 mM 5 mMMg2+ 0.5 mM 1-2 mMCa2+ 10-7 mM 1-2 mMH+ 10-7.2 M (pH 7.2) 10-7.4 M (pH 7.4)
Cl- 5-15 mM 110 mM
Resting Membrane Potential
Potassium ions, concentrated inside the cell tend to move outward down their concentration gradient through nongated potassium channels
the relative excess of negative charge inside the membrane tend to push potassium ions out of the cell
Potassium equilibrium-90 mV
Resting Membrane Potential
• But what about sodium?• Electrostatic and Chemical forces act together on
Na+ ions to drive them into the cell • The Na+ channel close during the resting state
Na+ is more concentrated outside than inside and therefore tends to flow into the cell down its concentration gradient
Na+ is driven into the cell by the electrical potential difference across the membrane.
Na+ electrochemical gradient
Equilibrium Potentials 平衡电位Theoretical voltage
produced across the membrane if only one kind of ion could diffuse through the membrane.
If membrane only permeable to K+, K+ diffuses until [K+] is at equilibrium.Force of electrical
attraction and diffusion are = opposite.
Calculating equilibrium potential
Nernst Equation
Allows theoretical membrane potential to be calculated for particular ion.Membrane potential that would exactly balance
the diffusion gradient and prevent the net movement of a particular ion.
Value depends on the ratio of [ion] on the 2 sides of the membrane.
Nernst equation
Equilibrium potential (mV) , Eion = lnRTzF
[C]o
[C]i
where,[C]o and [C]i = extra and intracellular [ion] R = Universal gas constant (8.3 joules.K-1.mol-1)T = Absolute temperature (°K)F = Faraday constant (96,500 coulombs.mol-1)z = Charge of ion (Na+ = +1, Ca2+ = +2, Cl- = -1)
For K+, with [K+]o = 4 mmol.l-1 and [K+]i = 150 mmol.l-1
At 37°C, EK = -97mV ENa = +60mv
1 10 100Extracellular potassium concentration (millimoles)
Membranepotential
(millivolts)
-130
-60
+10
(Red line shows valuesaccording to Nernst equation)
Experimental points
-70
5
[K+]o = 4 mmol.l-1
Resting Membrane Potential
less than Ek because some Na+ can also enter the cell.The slow rate of Na+ influx is accompanied by
slow rate of K+ outflux.Depends upon 2 factors:
Ratio of the concentrations of each ion on the 2 sides of the plasma membrane.
Specific permeability of membrane to each different ion.
ranges from - 65 to – 85 mV.
The Sodium-Potassium Pump钠 / 钾泵
• Dissipation of ionic gradients is ultimately prevented by Na+-K+ pumps
extrudes Na+ from the cell while taking in K
Resting Potential
Factors that affect resting potential
Difference of K+ ion concentration across the membrane
Permeability of the membrane to Na+ and K+.
Action of Na+ pump
Basic Electrophysiological Terms I:
Polarization 激化 : a state in which membrane is polarized at rest, negative inside and positive outside.
Depolarization 去极化 : the membrane potential becomes less negative than the resting potential (close to zero).
Hyperpolarization 超级化 : the membrane potential is more negative than the resting level.
Basic Electrophysiological Terms I:
Reverspolarization 反激化 : a reversal of membrane potential polarity.
The inside of a cell becomes positive relative to the outside.
Repolarization 复极 : restoration of normal polarization state of membrane.
the membrane potential returns from depolarized level to the normal resting membrane value.
Part 3 Action Potential 动作电位
Successive Stages:
(1) Resting Stage
(2) Depolarization stage
(3) Repolarization stage
(4) After-potential stage
(1)
(2) (3)
(4)
Concept
Action potential is a rapid, reversible 可逆转 , and conductive change of the membrane potential after the cell is stimulated.
Nerve signals are transmitted by action potentials.
Action Potential
Sequence
• Voltage-gated Na+ Channels open and Na+ rushes into the cell
Action Potential
Sequence
• At about +30 mV, Sodium channels close, but voltage-gated potassium channels open, causing an outflow of potassium, down its electrochemical gradient
Action Potential
Sequence
equilibrium potential of the cell is restored
Action Potential
Sequence
• The Sodium – Potassium Pump is left to clean up the mess…
Ion Permeability during the APIon Permeability during the AP
Figure 8-12: Refractory periods
Basic Electrophysiological Terms II (1)
Excitability 兴奋性 : The ability of the cell to generate the action potential
Excitable cells 可兴奋细胞 : Cells that generate action potential during excitation. in excitable cells (muscle, nerve, secretary cells), the
action potential is the marker of excitation.
Some scholars even suggest that in excitable cells, action potential is identical to the excitation.
Basic Electrophysiological Terms II (2)
Stimulus 刺激 : a sudden change of the (internal or external) environmental condition of the cell. includes physical and chemical stimulus. The electrical stimulus is often used for the
physiological research. Threshold 阈值 (intensity): the lowest or
minimal intensity of stimulus to elicit an action potential(Three factors of the stimulation: intensity,
duration, rate of intensity change)
Basic Electrophysiological Terms II (3)
Types of stimulus:
Threshold stimulus 阈刺激 : The stimulus with the intensity equal to threshold
Subthreshold stimulus 阈下刺激 : The stimulus with the intensity weaker than the threshold
Suprathreshold stimulus 阈上刺激 : The stimulus with the intensity greater than the threshold.
Action Potential Summary
Reduction in membrane potential (depolarization) to "threshold" level leads to opening of Na+ channels, allowing Na+ to enter the cell
Interior becomes positive The Na+ channels then close automatically
followed by a period of inactivation. K+ channels open, K+ leaves the cell and the
interior again becomes negative. Process lasts about 1/1000th of a second.
Properties of the Action Potential
“All or none” phenomenon with constant amplitude, time course and
propagation velocity in one cell.
Propagation Transmitted in both direction in a nerve
fiber
Squid giant axon
Gated channel states
CO2H
Outside
NH2
+++
+++
+++
+++
Inside
Na+ Channel -Subunit Structure
I II III IV
RVIRLARIGRILRLIKGAKGIR+ + + + + + + +
IFM
IFM
- Inactivation “Gate” IVS4 Voltage Sensor
NH2
CO
2 H
Voltage gated
But “ready” Not “ready”
Activation & Fast Inactivation
Sodium Activation and Inactivation Sodium Activation and Inactivation Variable vs VoltageVariable vs Voltage
Activation GateActivation Gate Inactivation gateInactivation gate
If resting potential depolarized by 15 – 20 mV, then activation gate opened with 5000x increase in Na+ permeability followed by inactivation gate close 1 ms later
Positive feedback loop
Reach “threshold”?
If YES, then...
Stimulation
Action potential initiation
S.I.Z.
Action potential termination
Threshold Potential 阈电位 plays a key role in the genesis of action potential.
a critical membrane potential level at which an action potential can occur.
dependent on the gating property of the voltage-gated Na+ channels.
most excitable cell : about 15 to 20 mV less negative than the resting potential.
The threshold stimulus is just strong enough to depolarize the membrane to the threshold potential level, therefore it can cause an action potential.
Electrophysiological Method to Record Membrane Potential I
Voltage Clamp 电压钳
Th
e Nob
el Prize in
Ph
ysiology or Med
icine (1963)
“for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane”
Alan Lloyd Hodgkin Andrew Fielding Huxley
a method for maintaining Vm at any desired voltage level (FBA, Feedback Amplifier)
The voltage clamp
The Hodgkin-Huxley Model of Action Potential Generation
Triphasic response
Evidence for a Sodium Current
Remove extracellular sodium
Modern proof of
nature of currents
Use ion selective agents
Removing Na+ from the bathing medium, INa becomes negligible so IK can be measured directly.
Subtracting this current from the total current yielded INa.
Conductance of Na+ and K+ channels
Voltage-Dependence of Conductance
An action potential gNa increases quickly, but then inactivation kicks in and it decreases again.
gK increases more slowly, and only decreases once the voltage has decreased.
The Na+ current is autocatalytic. An increase in V increases gNa , which increases the Na+ current, and increases V, etc.
Hence, the threshold for action potential initiation is where the inward Na+ current exactly balances the outward K+ current.
"for their discoveries concerning the function of single ion channels in cells"
Th
e Nob
el Prize in
Ph
ysiology or Med
icine (1991)
Erwin Neher Bert Sakmann
Cytoplasm Ion channels
"Giga-seal"
Glassmicroelectrode
Suction
1 µm
Patch clamp 膜片钳 recording
Cell Membrane
100 ms
4 pA
Closed
Open
Single channel record
Voltage-dependent Channel Conductance
How channel conductances accumulate
Next page shows an idealized version
Inactivating Na+ channel currents
Part 3 Nerve Conduction
• Local Response and Summation
• Nerve Conduction
Local Response Definition:
a small change in membrane potential caused by a subthreshold stimulus
Properties: a graded potential Propagation: electronic conduction be summed by two ways
Spatial summation Temporal summation
Graded (local)
potential changes
2 x more chemical= 2 x more potential
change
Excitatory
Excitatory
Inhibitory
Time
Mem
bra
ne P
ote
nti
al (
mV
)
Spatial Summation
Spatial Summation
a
b
c
d
a
b
c
d
Excitatory
Excitatory
Inhibitory
Time
Mem
bra
ne P
ote
nti
al (
mV
)
Temporal & Spatial Summation
Temporal Summation
a
b
c
d
a
b
c
d
Distribution of channels
Leak channels everywhere
Axon Hillock(Trigger Zone)
Role of the Local Potential
Facilitate the cell. increase excitability of the stimulated
cell
Cause the cell to excite once it is summed to reach the threshold potential
Propagation of the Action Potential
Myelinated neuron of the central nervous system
Saltatory conduction 跳跃式传导 : The action potential jumps from node to node
Saltatory Conduction
Saltatory Conduction
The pattern of conduction in the myelinated nerve fiber from node to node
It is of value for two reasons: very fast conserves energy.
Factors that affect the propagation
Bioelectric properties of the membrane
Velocity and amplitude of membrane depolarization
Part 4 Synaptic Transmission
• Chemical synapse (Classical Synapse)– Predominates in the vertebrate nervous
system
• 2.Non-synaptic chemical transmission• 3.Electrical synapse
– Via specialized gap junctions– Does occur, but rare in vertebrate NS– Astrocytes can communicate via gap
junctions
Chemical Synapse
• Terminal bouton is separated from postsynaptic cell by synaptic cleft.
• Vesicles fuse with axon membrane and NT released by exocytosis.
• Amount of NTs released depends upon frequency of AP.
Non-synaptic chemical transmission
The postganglionic neurons innervate the smooth muscles.
No recognizable endplates or other postsynaptic specializations;
The multiple branches are beaded with enlargements (varicosities) that are not covered by Schwann cells and contain synaptic vesicles;
Fig. : Ending of postganglionic autonomic neurons on smooth muscle
In noradrenergic neurons, the varicosities are about 5m, with up to 20,000 varicosities per neuron;
Transmitter is apparently released at each varicosity, at many locations along each axon;
One neuron innervate many effector cells.
Fig. : Ending of postganglionic autonomic neurons on smooth muscle
Non-synaptic chemical transmission continued
Electrical Synapse• Impulses can be regenerated
without interruption in adjacent cells.
• Gap junctions:– Adjacent cells electrically
coupled through a channel.
– Each gap junction is composed of 12 connexin proteins.
• Examples:– Smooth and cardiac
muscles, brain, and glial cells.
•Electric current flow- communication takes place by flow of electric current directly from one neuron to the other
•No synaptic cleft or vesicles cell membranes in direct contact
•Communication not polarized- electric current can flow between cells in either direction
Electrical Synapses
Electrical Synapse Chemical SynapsePurves, 2001
The Chemical Synapse and Signal Transmission
• The chemical synapse is a specialized junction that transfers nerve impulse information from a pre synaptic membrane to a postsynaptic membrane using neurotransmitters and enzymes
Synaptic connections
• ~100,000,000,000 neurons in human brain
• Each neuron contacts ~1000 cells
• Forms ~10,000 connections/cell
• How many synapses?
•Neurotransmitter- communication via a chemical intermediary called a neurotransmitter, released from one neuron and influences another
•Synaptic cleft- a small gap between the sending (presynaptic) and the receiving (postsynaptic) site
Chemical Synapses
•Synaptic vesicles- small spherical or oval organelles contain chemical transmitter used in transmission
•Polarization- communication occurs in only one direction, from sending presynaptic site, to receiving postsynaptic site
Chemical Synapses
• Precursor transport
• NT synthesis
• Storage
• Release
• Activation
• Termination ~diffusion, degradation, uptake, autoreceptors
1. Synaptic Transmission Model
PresynapticAxon Terminal
PostsynapticMembrane
Terminal Button Dendritic
Spine
(1) Precursor Transport
_ _ _
NT
(2) Synthesis
enzymes/cofactors
(3) Storage
in vesicles
Synapse
Vesicles
NT
Terminal Button Dendritic
Spine
Synapse
Terminal Button Dendritic
Spine
(4) Release
Receptors
Synapse
Terminal Button Dendritic
Spine
AP
Ca2+
Exocytosis
Each vesicle contains one quanta of neurotransmitter (approximately 5000 molecules) – quanta release
(5) Activation
(6) Termination
(6.1) Termination by... Diffusion
(6.2) Termination by...Enzymatic degradation
(6.3) Termination by... Reuptake
(6.4) Termination by... Autoreceptors
A
Autoreceptors
• On presynaptic terminal
• Binds NT
same as postsynaptic receptors
different receptor subtype
• Decreases NT release & synthesis
• Metabotropic receptors
Synaptic Transmission
• AP travels down axon to bouton.• VG Ca2+ channels open.
– Ca2+ enters bouton down concentration gradient.
– Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTs.
• Ca2+ activates calmodulin, which activates protein kinase.
• Protein kinase phosphorylates synapsins.– Synapsins aid in the fusion of synaptic vesicles.
Synaptic Transmission (continued)
• NTs are released and diffuse across synaptic cleft.
• NT (ligand) binds to specific receptor proteins in postsynaptic cell membrane.
• Chemically-regulated gated ion channels open.– EPSP: depolarization.– IPSP: hyperpolarization.
• Neurotransmitter inactivated to end transmission.
2 EPSP and IPSP
(1)Excitatory postsynaptic
potential (EPSP)An AP arriving in the presynaptic terminal cause the release of neurotransmitter;The molecules bind and active receptor on the postsynaptic membrane;
(1)Excitatory postsynaptic
potential (EPSP)Opening transmitter-gated ions channels ( Na+) in postsynaptic- membrane;Both an electrical and a concentration gradient driving Na+ into the cell; The postsynaptic membrane will become depolarized(EPSP).
EPSP• No threshold.• Decreases resting
membrane potential.– Closer to threshold.
• Graded in magnitude.
• Have no refractory period.
• Can summate.
(2) Inhibitory postsynaptic potential (IPSP)
• A impulse arriving in the presynaptic terminal causes the release of neurotransmitter;
•The molecular bind and active receptors on the postsynaptic membrane open CI- or, sometimes K+ channels;
• More CI- enters, K+ outer the cell, producing a hyperpolarization in the postsynaptic membrane.
•(IPSPs):–No threshold.
–Hyperpolarize postsynaptic membrane.
–Increase membrane potential.
–Can summate.
–No refractory period.
3 Synaptic Inhibition
• Presynaptic inhibition:– Amount of
excitatory NT released is decreased by effects of second neuron, whose axon makes synapses with first neuron’s axon.
• Postsynaptic inhibition
Concept: effect of inhibitory synapses on
the postsynaptic membrane. Mechanism: IPSP, inhibitory interneuron Types:
Afferent collateral inhibition( reciprocal
inhibition)
Recurrent inhibition.
(1) Postsynaptic inhibition
1) Reciprocal inhibition
Activity in the afferent fibers from the muscle spindles (stretch receptors) excites (EPSPs) directly the motor neurons supplying the muscle from which the impulses come.
Postsynaptic inhibition
At the same time, inhibits (ISPSs) those motor neurons supplying its antagonistic muscles.
1) Reciprocal inhibition
The latter response is mediated by branches of the afferent fibers that end on the interneurons.
Postsynaptic inhibition
The interneurons, in turn, secrete the inhibitory transmitter (IPSP) at synapses on the proximal dendrites or cell bodies of the motor neurons that supply the antagonist.
Neurons may also inhibit
themselves in a negative feedback
fashion.
Each spinal motor neuron regularly
gives off a recurrent collateral that
synapses with an inhibitory
interneuron which terminates on
the cell body of the spinal neuron
and other spinal motor neurons.
The inhibitory interneuron to
secrete inhibitory mediator, slows
and stops the discharge of the
motor neuron.
2) Recurrent inhibition
Postsynaptic inhibition
Concept: the inhibition occurs at the
presynaptic terminals before the
signal ever reaches the synapse.
The basic structure: an axon-axon
synapse (presynaptic synapse), A
and B.
Neuron A has no direct effect on
neuron C, but it exert a
Presynaptic effect on ability of B
to Influence C.
The presynatic effect May decrease
the amount of neuro- transmitter
released from B (Presynaptic
inhibition) or increase it
(presynaptic facilitation).
(2) Presynaptic inhibition
AAB
C
A
C
B
The mechanisms:
• Activation of the presynaptic receptors increases CI- conductance,
to decrease the size of the AP reaching the excitatory ending,
reduces Ca2+ entry and consequently the amount of excitatory transmitter decreased.
Presynaptic inhibition
• Voltage-gated K+ channels are also opened, and the resulting K+ efflux also decreases the Ca2+ influx.
Excitatory Synapse
• A active
• B more likely to fire
• Add a 3d neuron ~
A B+
Presynaptic Inhibition
Excitatory Synapse
• Axon-axon synapse
• C is inhibitory ~
A B+
Presynaptic Inhibition
C
-
Excitatory Synapse
A B+
Presynaptic Inhibition
C
-
• C active
• less NT from A when active
• B less likely to fire ~
4 Synaptic Facilitation: Presynaptic and Postsynaptic
Excitatory Synapse
• A active
• B more likely to fire ~
A B+
(1) Presynaptic Facilitation
Excitatory Synapse
A B+
Presynaptic Facilitation
C
+
• C active (excitatory)• more NT from A when
active (Mechanism:AP of A is prolonged and Ca 2+ channels are open for a longer period.)
• B more likely to fire ~
(2) Postsynaptic facilitation: neuron that has been partially depolarized is more likely to undergo AP.
-65mv
- 70mv AT REST
Vm
Time
EPSP
+
-
• Depolarization
more likely to fire ~
Record here
+
5 Synaptic Integration
• EPSPs can summate, producing AP.– Spatial summation:
• Numerous PSP converge on a single postsynaptic neuron (distance).
– Temporal summation: • Successive waves of
neurotransmitter release (time).
(1) Spatial Summation
• The accumulation of neurotransmitter in the synapse due the combined activity of several presynaptic neurons entering the Area (Space) of a Convergent Synapse.
• A space (spatial) dependent process.
-65mv
- 70mv AT REST
vm
Time
+
-
SpatialSummation +
• Multiple synapses
+
(2) Temporal Summation
• The accumulation of neurotransmitters in a synapse due to the rapid activity of a presynaptic neuron over a given Time period.
• Occurs in a Divergent Synapse. (explain later)
• Is a Time (Temporal) dependent process.
-65mv
- 70mv AT REST
Vm
Time
+
-
TemporalSummation
+
Repeated stimulation same synapse ~
(3) EPSPs & IPSPs summate
• CANCEL EACH OTHER
• Net stimulation – EPSPs + IPSPs = net effects ~
- 70mv
+
-
-
EPSP
IPSP
+
6. Divergent and Convergent Synapse
Divergent Synapse
•A junction that occurs between a presynaptic neuron and two or more postsynaptic neurons (ratio of pre to post is less than one).
•The stimulation of the postsynaptic neurons depends on temporal summation).
Convergent Synapse
Presynaptic neurons
Postsynaptic neuron
•A junction between two or more presynaptic neurons with a postsynaptic neuron (the ratio of pre to post is greater than one).
•The stimulation of the postsynaptic neuron depends on the Spatial Summation.
Section 3 Neurotransmitters and Receptors
1. Basic Concepts of NT and receptor
Neurotransmitter: Endogenous signaling molecules that alter the behaviour of neurons or effector cells.
Neuroreceptor: Proteins on the cell membrane or in the cytoplasm that could bind with specific neurotransmitters and alter the behavior of neurons of effector cells
•Vast array of molecules serve as neurotransmitters
•The properties of the transmitter do not determine its effects on the postsynaptic cells
•The properties of the receptor determine whether a transmitter is excitatory or inhibitory
A neurotransmitter must (classical definition)
• Be synthesized and released from neurons• Be found at the presynaptic terminal• Have same effect on target cell when applied externally• Be blocked by same drugs that block synaptic transmission• Be removed in a specific way
Purves, 2001
Synaptic vesicles
• Concentrate and protect transmitter
• Can be docked at active zone
• Differ for classical transmitters (small, clear-core) vs. neuropeptides (large, dense-core)
Classical Transmitters (small-molecule transmitters)•Biogenic Amines
•Acetylcholine
•Catecholamines
•Dopamine
•Norepinerphrine
•Epinephrine
•Serotonin
•Amino Acids
•Glutamate
•GABA (-amino butyric acid)
•Glycine
•Neuropeptides
•Neurotrophins
•Gaseous messengers
–Nitric oxide
–Carbon Monoxide
•D-serine
Non-classical Transmitters
Peripheral Neurotransmitters
• Acetylcholine and Norepinephrine
• All preganglionic neurons are cholinergic
• Parasympathetic post ganglionic neurons are cholinergic
• Sympathetic post ganglionic neurons are adrenergic except
• Sympathetics innervating sweat glands, blood vessels in skeletal muscle, and piloerection muscles are cholinergic
Nerve Fibers that release Ach and NE in PNS
ACh AChSweatglands
Striatedmuscle
AChSOMATIC NERVOUS SYSTEM
HeartSm. mus.Glands
ACh AChParasympathetic
ACh E, NE
Ad. M.
HeartSm. mus.Glands
ACh NE
AUTONOMIC NERVOUS SYSTEM
Sympathetic
Neurotransmitters in CNS
• Major Excitatory and Inhibitory Neurotransmitters– Excitatory: glutamate– Inhibitory: γ-aminobutyric acid (GABA)
• Neuromodulators– NE, 5-HT, serotonin, peptides
• Gastrous Neurotransmitter– NO, CO, H2S
Neurotransmitter Co-existence (Dale principle)Some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a catecholamine) and a polypeptide neurotransmitter.
They are contained in different synaptic vesicles that can be distinguished using the electron microscope.
The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions.
Purves, 2001
Agonist
A substance that mimics a specific neurotransmitter,
is able to attach to that neurotransmitter's receptor
and thereby produces the same action that the neurotransmitter usually produces.
Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted.
Antagonist
Drugs that bind to but do not activate neuroreceptors,
thereby blocking the actions of neurotransmitters or the neuroreceptor agonists.
Receptor BReceptor A
• Same NT can bind to different -R
• different part of NT ~
NT
NT
Specificity of drugs
Drug ADrug B
Receptor BReceptor A
Five key steps in neurotransmission
• Synthesis
• Storage
• Release
• Receptor Binding
• Inactivation
Purves, 2001
Receptors determine whether:• Synapse is excitatory or inhibitory
– NE is excitatory at some synapses, inhibitory at others
• Transmitter binding activates ion channel directly or indirectly.– Directly
• ionotropic receptors• fast
– Indirectly• metabotropic receptors• G-protein coupled• slow
2. Receptor Activation
• Ionotropic channel– directly controls channel– fast
• Metabotropic channel– second messenger systems– receptor indirectly controls channel ~
(1) Ionotropic ChannelsneurotransmitterNTChannel
Ionotropic Channels
NT
Pore
Ionotropic Channels
NT
Ionotropic Channels
NT
(2) Metabotropic Channels
• Receptor separate from channel
• G proteins
• 2d messenger system– cAMP– other types
• Effects– Control channel– Alter properties of receptors– regulation of gene expression ~
(2.1) G protein: direct control
• NT is 1st messenger
• G protein binds to channel– opens or closes– relatively fast ~
G protein: direct control
RG
GDP
G protein: direct control
RG
GTP
Pore
(2.2) G protein: Protein Phosphorylation
Receptor
trans-ducer
primaryeffector
external signal: nt
2d messenger
secondary effector
Receptor
trans-ducer
primaryeffector
external signal: NT
2d messenger
secondary effector
GS
norepinephrine
cAMP
protein kinase
adrenergic -R
adenylylcyclase
G protein: Protein Phosphorylation
RG
GDP
AC
PK
G protein: Protein Phosphorylation
R
AC
PK
G
GTPATP
cAMP
G protein: Protein Phosphorylation
R
AC
PK
G
GTPATP
cAMP
P
Pore
(3) Transmitter Inactivation
• Reuptake by presynaptic terminal
• Uptake by glial cells
• Enzymatic degradation
• Presynaptic receptor
• Diffusion
• Combination of above
Neurotransmitter Reuptake by Na+ dependent (linked) transporters
Summary of Synaptic
Transmission
Purves,2001
Basic Neurochemistry
Receptor Desensitization
• Phosphorylation of the receptor and combined by arrestin
• Receptor endocytosis (internalization)
GPLR 的失敏:
例:肾上腺素受体被激活后, 10-15 秒 cAMP 骤增,然后在不到 1min 内反应速降,以至消失。
受体活性快速丧失(速发相) --- 失敏( desensitization ); 机制:受体磷酸化 受体与 Gs 解偶联, cAMP 反应停止并被 PDE 降解。 两种 Ser/Thr 磷酸化激酶: PKA 和肾上腺素受体激酶( ARK ), 负责受体磷酸化; 胞内协作因子扑获蛋白( arrestin ) --- 结合磷酸化的受体,抑制其功能
活性( arrestin 已克隆、定位 11q13 )。 反应减弱(迟发相) --- 减量调节( down-regulation ) 机制:受体 - 配体复合物内吞,导致表面受体数量减少,发现
arrestin 可直接与 Clathrin 结合,在内吞中起 adeptors 作用; 受体减量调节与内吞后受体的分选有关。
3. Some Important Transmitters
(1) Acetylcholine (ACh) as NT
Acetylcholine Synthesis
choline + acetyl CoA ACh + CoA
cholineacetyltransferase
Acetylcholinesterase (AChE)
• Enzyme that inactivates ACh.
– Present on postsynaptic membrane or immediately outside the membrane.
• Prevents continued stimulation.
The Life Cycle of Ach
Ach - Distribution
• Peripheral N.S.• Excites somatic skeletal muscle (neuro-muscular
junction)• Autonomic NS
Ganglia
Parasympathetic NS--- Neuroeffector junction
Few sympathetic NS – Neuroeffector junction
• Central N.S. - widespreadHippocampus
Hypothalamus ~
•ACh is both an excitatory and inhibitory NT, depending on organ involved.
–Causes the opening of chemical gated ion channels.
•Nicotinic ACh receptors:
–Found in autonomic ganglia (N1) and skeletal muscle fibers (N2).
•Muscarinic ACh receptors:
–Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands .
Ach Receptors
Acetylcholine Neurotransmission
• “Nicotinic” subtype Receptor:– Membrane Channel for Na+ and K+
– Opens on ligand binding– Depolarization of target (neuron, muscle)– Stimulated by Nicotine, etc.– Blocked by Curare, etc.– Motor endplate (somatic) (N2), – all autonomic ganglia, hormone
producing cells of adrenal medulla (N1)
Acetylcholine Neurotransmission
• “Muscarinic” subtype Receptor: M1
– Use of signal transduction system
• Phospholipase C, IP3, DAG, cytosolic Ca++
– Effect on target: cell specific (heart , smooth muscle intestine )
– Blocked by Atropine, etc.– All parasympathetic target organs– Some sympathetic targets (endocrine sweat
glands, skeletal muscle blood vessels - dilation)
Acetylcholine Neurotransmission
• “Muscarinic” subtype: M2
– Use of signal transduction system• via G-proteins, opens K+ channels, decrease
in cAMP levels– Effect on target: cell specific– CNS – Stimulated by ?– Blocked by Atropine, etc.
Cholinergic Agonists
• Direct– Muscarine – Nicotine
• Indirect– AChE Inhibitors ~
Cholinergic Antagonists
• Direct
Nicotinic - Curare
Muscarinic - Atropine
Ligand-Operated ACh Channels
N Receptor
G Protein-Operated ACh ChannelM receptor
(2) Monoamines as NT
Monoamines
• Catecholamines –
Dopamine - DA
Norepinephrine - NE
Epinephrine - E
• Indolamines - Serotonin - 5-HT
Mechanism of Action ( receptor)
Epi1
G protein
PLC IP3
Ca+2
Norepinephrine (NE) as NT
• NT in both PNS and CNS.
• PNS: – Smooth muscles, cardiac muscle and glands.
• Increase in blood pressure, constriction of arteries.
• CNS:– General behavior.
Adrenergic Neurotransmission
1 Receptor– Stimulated by NE, E, – blood vessels of skin, mucosa, abdominal
viscera, kidneys, salivary glands – vasoconstriction, sphincter constriction, pupil
dilation
Adrenergic Neurotransmission2 Receptor
– stimulated by, NE, E, …..– Membrane of adrenergic axon terminals (pre-
synaptic receptors), platelets– inhibition of NE release (autoreceptor), – promotes blood clotting, pancreas decreased
insulin secretion
Adrenergic Neurotransmission
• 1 receptor– stimulated by E, ….– Mainly heart muscle cells, – increased heart rate and strength
Adrenergic Neurotransmission
• 2 receptor– stimulated by E ..– Lungs, most other sympathetic organs, blood
vessels serving the heart (coronary vessels),– dilation of bronchioles & blood vessels
(coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus
Adrenergic Neurotransmission
• 3 receptor– stimulated by E, …. – Adipose tissue, – stimulation of lipolysis
(3) Amino Acids as NT
• Glutamate acid and aspartate acid:– Excitatory Amino Acid (EAA)
• gamma-amino-butyric acid (GABA) and glycine:– Inhibitory AA
(4) Polypeptides as NT
• CCK:– Promote satiety following meals.
• Substance P:– Major NT in sensations of pain.
(5) Monoxide Gas: NO and CO
• Nitric Oxide (NO)– Exerts its effects by stimulation of cGMP.– Involved in memory and learning. – Smooth muscle relaxation.
• Carbon monoxide (CO):– Stimulate production of cGMP within neurons.– Promotes odor adaptation in olfactory neurons.– May be involved in neuroendocrine regulation in
hypothalamus.