Neuromuscular Engineering 1 Neuromuscular Engineering & Technology IsoCOG.
Neuromuscular transmission
-
Upload
drrahulkumarsingh -
Category
Health & Medicine
-
view
423 -
download
3
description
Transcript of Neuromuscular transmission
![Page 1: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/1.jpg)
![Page 2: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/2.jpg)
![Page 3: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/3.jpg)
![Page 4: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/4.jpg)
Anatomy
Critical to function
![Page 5: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/5.jpg)
![Page 6: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/6.jpg)
![Page 7: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/7.jpg)
![Page 8: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/8.jpg)
10m 10m
NMJ on the muscle fiber
![Page 9: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/9.jpg)
![Page 10: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/10.jpg)
Synaptic selectivity at developing NMJ
![Page 11: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/11.jpg)
![Page 12: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/12.jpg)
Synapse from a frog sartorius neuromuscular junction showing vesicles clustered in the active zone, some docked at the membrane (arrows). (from Heuser, 1977)
![Page 13: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/13.jpg)
Synaptic Transmission
The Steps
![Page 14: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/14.jpg)
• Precursor transport• NT synthesis• Storage• Release• Activation• Termination ~diffusion, degradation,
uptake, autoreceptors
Synaptic Transmission Model
![Page 15: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/15.jpg)
PresynapticAxon Terminal
PostsynapticMembrane
Terminal Button
![Page 16: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/16.jpg)
(1) Precursor Transport
![Page 17: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/17.jpg)
_ _ _
NT
(2) Synthesis
enzymes/cofactors
![Page 18: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/18.jpg)
(3) Storage
in vesicles
![Page 19: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/19.jpg)
A quantum is the number of transmitters released from a single synaptic vesicle
Vesicles have a fairly uniform size and diameter ≈ 40- 50 nm
Individual vesicles contain 8000 - 10,000 phospholipid molecules and several proteins. The vesicle molecular weight is approx. 3-5 x 106
![Page 20: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/20.jpg)
![Page 21: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/21.jpg)
Proteins associated with synaptic vesicles(identified through sequencing and cloning of cDNA’s)
Membrane proteinsA. Synaptophysin (~ 36 kD)B. Synaptotagmin (~ 61 kD; the Ca2+ sensor)C. Snares (residents of either the vesicle [v-snare] or the target membrane [t-snare])
1. VAMP (also called synaptobrevin), a v-snare (~18 kD)2. Syntaxin, a t-snare that also associates with Ca2+
channels (~32 kD; technically not a vesicle protein)3. SNAP-25, a t-snare (~25 kD; also technically not a
vesicle protein)D. Electrogenic proton ATPase -creates emf that drives
neurotransmitter uptake against a concentration gradient
![Page 22: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/22.jpg)
Proteins associated with synaptic vesicles(identified through sequencing and cloning of cDNA’s)
Membrane proteinsA. Synaptophysin (~ 36 kD)B. Synaptotagmin (~ 61 kD; the Ca2+ sensor)C. Snares (residents of either the vesicle [v-snare] or the target membrane [t-snare])
1. VAMP (also called synaptobrevin), a v-snare (~18 kD)2. Syntaxin, a t-snare that also associates with Ca2+
channels (~32 kD; technically not a vesicle protein)3. SNAP-25, a t-snare (~25 kD; also technically not a
vesicle protein)D. Electrogenic proton ATPase -creates emf that drives
neurotransmitter uptake against a concentration gradient
![Page 23: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/23.jpg)
An alternative form of Ca2+-dependent vesicle fusion, termed fast tracking, or “kiss and run” predominates at low frequency stimulation.
![Page 24: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/24.jpg)
Life cycle of a synaptic vesicle
![Page 25: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/25.jpg)
![Page 26: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/26.jpg)
![Page 27: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/27.jpg)
Synapse
Terminal Button
Dendritic Spine
![Page 28: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/28.jpg)
Synapse
Terminal Button
Dendritic Spine
(4) Release
Receptors
![Page 29: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/29.jpg)
Synapse
Terminal Button
Dendritic Spine
AP
![Page 30: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/30.jpg)
Ca2+
Exocytosis
![Page 31: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/31.jpg)
From Kristin Harris Lectures.http://synapses.mcg.edu/lab/harris/lectures.htm
![Page 32: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/32.jpg)
![Page 33: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/33.jpg)
1X
4X
2X
Stimulation
1 mV
1X
2X
3X
4X
mini Mini histogram.
Evoked amplitudes.
Squire Fund. Neurosci.
![Page 34: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/34.jpg)
From Kristin Harris Lectures.http://synapses.mcg.edu/lab/harris/lectures.htm
![Page 35: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/35.jpg)
Electron micrographs of “omega figures” (fusing synaptic vesicles) after slam freezing a firing synapse provided clinching evidence for the vesicle hypothesis.
No firing
Firing
Heuser and Reese, 1981
“docked”
“fast”“slow”
![Page 36: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/36.jpg)
A cholinergic synapseNerve fiber (axon)
Action potential
Choline
Na+, Cl-
Acetyl-CoA
Acetyl-Choline
Acetyl-Choline
Ca + +
Ca + +
![Page 37: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/37.jpg)
A cholinergic synapse (2): Rapid transmitter inactivation by cholinesterase
Acetyl-Choline
Cholineesterase
Acetate
Acetyl-CoA
Choline
Action potential
Ca + +
![Page 38: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/38.jpg)
(5) Activation
![Page 39: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/39.jpg)
![Page 40: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/40.jpg)
(1) Ionotropic ChannelsneurotransmitterNTChannel
![Page 41: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/41.jpg)
Ionotropic Channels
NT
Pore
![Page 42: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/42.jpg)
Ionotropic Channels
NT
![Page 43: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/43.jpg)
Ionotropic Channels
NT
![Page 44: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/44.jpg)
Acetylcholine Receptor
(or )
Miyazawa, A., Y. Fujiyoshi, and N. Unwin. 2003. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423:949-955.
ACh
ACh
![Page 45: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/45.jpg)
45
End Plate Potential (EPP)
Outside
Inside
Muscle membrane
Presynapticterminal M
uscl
e M
embr
ane
Volta
ge (m
V)Time (msec)
-90 mV
VK
VNa
0
Threshold
Presynaptic AP
EPP
The movement of Na+ and K+
depolarizes muscle membranepotential (EPP)
ACh Receptor Channels Voltage-gatedNa Channels Inward Rectifier
K Channels
![Page 46: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/46.jpg)
• Normally, the average EPP amplitude = 60 mV -In frog, ~150 vesicles
• Safety factor for transmission is therefore high (greater than 1) - Frog example: VEPP VAPthreshold
= 60 mV │-90 mV*- [-50 mV] │
= 60 mV 40 mV = 1.5
(*muscle resting VM = -90 mV)
Normal EPPs invariably evoke muscle action potentials
![Page 47: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/47.jpg)
(6) Termination
![Page 48: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/48.jpg)
(6.1) Termination by... Diffusion
![Page 49: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/49.jpg)
(6.2) Termination by...Enzymatic degradation
![Page 50: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/50.jpg)
Acetylcholine Metabolism
AChacetylcholine
esterase (AChE)choline + acetate
• AChE is located in the synaptic cleft• Choline is taken back up into the presynaptic terminal – active process• Acetate diffuses away to be utilized in other metabolic roles
![Page 51: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/51.jpg)
(6.3) Termination by... Reuptake
![Page 52: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/52.jpg)
(6.4) Termination by... Autoreceptors
A
![Page 53: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/53.jpg)
![Page 54: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/54.jpg)
The Safety Factor !!!
• Number of Quanta
• The receptor density on the post synaptic membrane
• The activity of ACH esterase
• The folds of the PS membrabe
• The presence of active zones
![Page 55: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/55.jpg)
![Page 56: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/56.jpg)
![Page 57: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/57.jpg)
Voltage-gated channels
![Page 58: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/58.jpg)
Na+ channelopathies
Gene Channel Disease
Muscle SCN4A subunit of NaV1.4 Hyperkalaemic periodic paralysisHypokalaemic periodic paralysisParamyotonia congenitaPotassium-aggravated myotoniaMyotonia fluctuansMyotonia permanensetc
Neuronal SCN1A subunit of NaV1.1
(somatic)
Generalised Epilepsy with Febrile Seizures + (GEFS+), Severe myoclonic epilepsy of infancy (SMEI)
SCN2A subunit of NaV1.2
(axonal)
GEFS+
SCN1B 1 subunit
![Page 59: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/59.jpg)
Ca2+ channel structure
2
1
![Page 60: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/60.jpg)
Ca2+ channelopathies
Gene Channel Disease
Muscle CACNA1S subunit of CaV1.1 HypoK periodic paralysisMalignant hyperthermia
RYR1 Ryanodine receptor (sarcoplasmic channel)
Malignant hyperthermiaCentral core disease
Neuronal CACNA1A subunit of CaV2.1
(P/Q-type channel)
Familial hemiplegic migraineEpisodic ataxia type 2Spinocerebellar ataxia type 6Absence epilepsy?
CACNA1H subunit of CaV3.2
(T-type channel)
Absence epilepsy
![Page 61: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/61.jpg)
Nicotinic receptor channelopathies
Gene Channel Disease
Muscle CHRNA1 1 subunit Congenital myasthenic syndrome
CHRNB1 1 subunit
CHRND subunit
CHRNE subunit
Neuronal CHRNA2 4 subunit AD nocturnal frontal lobe epilepsy
CHRNB4 2 subunit
![Page 62: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/62.jpg)
Slow channel syndrome
Sine et al (1995)
![Page 63: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/63.jpg)
Fast channel syndrome can be associated with congenital joint deformities (arthrogryposis multiplex)
Brownlow et al (2001)
![Page 64: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/64.jpg)
![Page 65: Neuromuscular transmission](https://reader036.fdocuments.us/reader036/viewer/2022081511/55648585d8b42a361d8b4e68/html5/thumbnails/65.jpg)