Neuromuscular transmission

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Information about Neuromuscular transmission
Health & Medicine

Published on February 19, 2014

Author: drrahulkumarsingh

Source: slideshare.net

Description

Steps Of Neuromuscular Transmission, Synapse, Neuro-Muscular Junction, Quantal Release, Acetyl Choline Receptor Physiology

Anatomy Critical to function

NMJ on the muscle fiber 10µm 10µm

Synaptic selectivity at developing NMJ

Synapse from a frog sartorius neuromuscular junction showing vesicles clustered in the active zone, some docked at the membrane (arrows). (from Heuser, 1977)

Synaptic Transmission The Steps

Synaptic Transmission Model • • • • • • Precursor transport NT synthesis Storage Release Activation Termination ~diffusion, degradation, uptake, autoreceptors

Presynaptic Axon Terminal Terminal Button Postsynaptic Membrane

(1) Precursor Transport

(2) Synthesis _ _ _ enzymes/cofactors NT

(3) Storage in vesicles

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

Proteins associated with synaptic vesicles (identified through sequencing and cloning of cDNA’s) Membrane proteins A. B. C. Synaptophysin (~ 36 kD) Synaptotagmin (~ 61 kD; the Ca2+ sensor) 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 Ca 2+ 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

Proteins associated with synaptic vesicles (identified through sequencing and cloning of cDNA’s) Membrane proteins A. B. C. Synaptophysin (~ 36 kD) Synaptotagmin (~ 61 kD; the Ca2+ sensor) 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 Ca 2+ 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

An alternative form of Ca2+-dependent vesicle fusion, termed fast tracking, or “kiss and run” predominates at low frequency stimulation.

Life cycle of a synaptic vesicle

Terminal Button Dendritic Spine Synapse

(4) Release Terminal Button Dendritic Spine Synapse Receptors

Terminal Button AP Dendritic Spine Synapse

Exocytosis Ca2+

From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

Stimulation mini Evoked amplitudes. 1X 4X Mini histogram. 2X 1X 3X 4X 2X 1 mV Squire Fund. Neurosci.

From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

“docked” No firing “fast” “slow” Firing Heuser and Reese, 1981 Electron micrographs of “omega figures” (fusing synaptic vesicles) after slam freezing a firing synapse provided clinching evidence for the vesicle hypothesis.

A cholinergic synapse Ne rv Action potential Choline ef ibe r( ax on ) Na+, Cl- Acetyl-CoA Acetyl-Choline Ca + + Ca + + Acetyl-Choline

A cholinergic synapse (2): Rapid transmitter inactivation by cholinesterase Choline Acetate Action potential Acetyl-CoA Acetyl-Choline Ca + + Choline esterase

(5) Activation

(1) Ionotropic Channels Channel NT neurotransmitter

Ionotropic Channels NT Pore

Ionotropic Channels NT

Ionotropic Channels NT

Acetylcholine Receptor α β γ (or ε) ACh ACh δ α Miyazawa, A., Y. Fujiyoshi, and N. Unwin. 2003. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423:949-955.

End Plate Potential (EPP) Presynaptic terminal VNa Muscle Membrane Voltage (mV) The movement of Na+ and K+ depolarizes muscle membrane potential (EPP) 0 EPP Threshold -90 mV VK Presynaptic AP Time (msec) Outside Muscle membrane Inside ACh Receptor Channels Voltage-gated Na Channels Inward Rectifier K Channels 45

Normal EPPs invariably evoke muscle action potentials • 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)

(6) Termination

(6.1) Termination by... Diffusion

(6.2) Termination by... Enzymatic degradation

Acetylcholine Metabolism acetylcholine ACh 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

(6.3) Termination by... Reuptake

(6.4) Termination by... Autoreceptors A

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

Voltage-gated channels

Na+ channelopathies Gene Channel Disease Muscle SCN4A α subunit of NaV1.4 Hyperkalaemic periodic paralysis Hypokalaemic periodic paralysis Paramyotonia congenita Potassium-aggravated myotonia Myotonia fluctuans Myotonia permanens etc Neuronal SCN1A α subunit of NaV1.1 (somatic) Generalised Epilepsy with Febrile Seizures + (GEFS+), Severe myoclonic epilepsy of infancy (SMEI) SCN2A α subunit of NaV1.2 (axonal) GEFS+ SCN1B β1 subunit

Ca2+ channel structure α2δ γ β α1

Ca2+ channelopathies Gene Neuronal Disease CACNA1S α subunit of CaV1.1 HypoK periodic paralysis Malignant hyperthermia RYR1 Muscle Channel Ryanodine receptor (sarcoplasmic channel) Malignant hyperthermia Central core disease CACNA1A α subunit of CaV2.1 (P/Q-type channel) Familial hemiplegic migraine Episodic ataxia type 2 Spinocerebellar ataxia type 6 Absence epilepsy? CACNA1H αsubunit of CaV3.2 (T-type channel) Absence epilepsy

Nicotinic receptor channelopathies Gene CHRNA1 α1 subunit Congenital myasthenic syndrome β1 subunit CHRND δ subunit CHRNE Neuronal Disease CHRNB1 Muscle Channel ε subunit CHRNA2 α4 subunit CHRNB4 β2 subunit AD nocturnal frontal lobe epilepsy

Slow channel syndrome Sine et al (1995)

Fast channel syndrome can be associated with congenital joint deformities (arthrogryposis multiplex) Brownlow et al (2001)

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