Case released. ACh is transported in synaptic vesicles

CaseHistory:Kelly, a 12-year-old girl, has significant gait abnormalitiesresulting from cerebral palsy.

She walks on her toes and exhibits ascissor gait, with her legs strongly adducted with each step. Kellyhas shown no significant improvements in gait with standard therapy,including exercises, gait training, and training in activities ofdaily living. Her physicians now want to inject a small amount ofbotulinum toxin into the gastrocnemius and adductor magnus muscles ofboth legs in an effort to reduce involuntary muscle activity andimprove gait. By what mechanism could injection of botulinum toxin reduce involuntary muscle activity? AChis a neurotransmitter that is synthesised into acetyl coA andchlorine, catalyzed by choline acetyltransferase (CAT). Ina normal neuron (in this case at the neuromuscular junction), thearrival of an action potential at the axon terminal opensvoltage-gated calcium channels, allowingcalciumto enter the neuron. The entry of calcium causes ACh to be released.ACh is transported in synaptic vesicles to the presynaptic terminal.Three SNARE proteins allows the ACh molecules to be released into thesynaptic cleft (synaptic fusion complex) by binding the synapticvesicle onto the presynaptic membrane.

ACh is released into thesynaptic cleft. It then binds to the receptors on the post-synapticterminal causing a depolarization of the sarcolemma via T tubules,which carry the action potential along their surface. This opens thatvoltage-dependent calcium channels in the terminal cisternae.Troponin can then bind to the calcium, resulting in tropomyosinacting on the actin filament. This uncovers the myosin binding siteon the actin, and causes muscle fibre contraction for as long asthere is calcium available. Botulinumtoxin disrupts this process. It is a neurotransmitter antagonist thatworks by inhibiting the release of acetylcholine (ACh) into thesynaptic cleft from the presynaptic neuron at the neuromuscularjunction.

1Thebotulinum toxin moleculeconsists of a heavy chain and light chain. The heavy chain bindsirreversibly to the presynapticcholinergicneuron. The light chain detaches and then cleaves one of the threeSNARE proteins which prevents the binding to the synaptic vesiclecontainingACh tothe presynaptic membrane, thereby preventing the release of ACH intothe synaptic cleft. The sarcolemma is then not depolarized andtherefore the action potential is not propagated, and the musclecannot contract, reducing spasticity. Inthe case of Kelly,botulinum toxinwould work locally in the muscles that have been injected, preventingthe contraction of gastrocnemius and adductor magnus via themechanisms mentioned above, which in turn would lessen herspasticity. Clinical trials show good response tobotulinum toxinin children with cerebral palsy, with gait velocity showingsignificant increases.2,3 At the neuromuscular junction, ACh acts via a ligand-gated receptor. Is the action of ACh on the nicotinic, ligand-gated receptor the same as its action on the muscarinic, G-protein–mediated receptor? Broadlyspeaking, no.

Best services for writing your paper according to Trustpilot

Premium Partner
From $18.00 per page
4,8 / 5
4,80
Writers Experience
4,80
Delivery
4,90
Support
4,70
Price
Recommended Service
From $13.90 per page
4,6 / 5
4,70
Writers Experience
4,70
Delivery
4,60
Support
4,60
Price
From $20.00 per page
4,5 / 5
4,80
Writers Experience
4,50
Delivery
4,40
Support
4,10
Price
* All Partners were chosen among 50+ writing services by our Customer Satisfaction Team

The action of ACh on ligand-gated receptors is that itcauses a fast signal transmission at the synapse and a rapidpost-synaptic response by opening ion channels directly. In nicotinicreceptors, it acts as an excitatory neurotransmitter. These arenormally found in the neuromuscular junction, autonomic ganglia anddifferent areas of the CNS.4Theaction on muscarinic receptors tends to be a slower process that theaction on ligand-gated receptors. It can either act asan inhibitory or excitatory neurotransmitter. On muscarinicreceptors, it activated G-proteinswhich increase intracellular calcium as part of a intracellularcascade. The binding of ACh to the receptors causes them to changeshape, which causes the G-protein to then convert guanosinetriphosphate to guanosine diphosphate,hence becoming activated. This protein then stimulates enzymes tocatalyse further intracellular reactions via a secondary messengersystem.

Muscarinic receptors generally are involved in autonomiceffects on the heart (regulation of heart rate in cardiac muscle) andthe brain, and can have longer-lasting effects especially concerninggene expression. Interestingly, ACh is a neuromodulator that allowsimproved encoding of new stimuli5and therefore enhance the encoding of new memories.6 References: Nigam PK, Nigam A. Botulinum toxin. Indian journal of dermatology.

2010;55:8-14. Baker R, Jasinski M, Maciag-Tymecka I, et al. Botulinum toxin treatment of spasticity in diplegic cerebral palsy: a randomized, double-blind, placebo-controlled, dose-ranging study. Developmental Medicine and Child Neurology. 2002;44:666-675 Wissel J, Heinen F, Schenkel A, et al. Botulinum toxin A in the management of spastic gait disorders in children and young adults with cerebral palsy: a randomized, double-blind study of “high-dose” versus “low-dose” treatment.

Neuropediatrics. 1999;30:120. Lundy-Eckman L. Neuroscience: fundamentals for rehabilitation.

4th Ed. S.l.: Saunders; 2012. Dannenberg H, Young K, Hasselmo M.

Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors. Frontiers in Neural Circuits. 2017;11. doi:10.3389/fncir.

2017.00102. Hasselmo ME. The role of acetylcholine in learning and memory. Current Opinion in Neurobiology.

2006;16:710-715.

x

Hi!
I'm Dora!

Would you like to get a custom essay? How about receiving a customized one?

Click here