Acetylcholine Flashcards
What type of NT is ACh?
Amine.
How is ACh synthesised?
From acetyl CoA and choline, via the enzyme choline acetyltransferase (ChAT).
Which enzyme degrades ACh?
Acetylcholinesterase (AChE).
Which transporter is responsible for the reuptake of ACh into the presynaptic terminal?
Choline transporter (CHT1).
Where is choline found?
In high concentrations in the presynaptic terminal.
What are the two primary roles of ACh?
Elicits muscle contractions at the NMJ.
Acts as a neuromodulator for memory and sleep.
Name the three locations of cholinergic nuclei.
Nucleus basalis of Meynert.
Medial septum.
Brainstem.
Cell bodies in the nucleus basalis of Meynert and medial septum are vital to what?
Normal cognition and memory.
Where does the nucleus basalis of Meynert project to?
Cortex.
Where does the medial septum project to?
Hippocampus.
Cell bodies in the brainstem are important for what?
Sleep and motor control.
Where do cell bodies in the brainstem project to?
Diencephalon and basal ganglia.
From where and when are neuromodulators typically released?
Released from varicosities during en passant transmission.
Name two ACh agonists.
Nicotine.
Muscarine.
Name the five subunits of nicotinic acetylcholine receptors (nAChRs).
Alpha.
Beta.
Gamma.
Delta.
Epsilon.
How many alpha nAChR subunits are there?
10.
How many beta nAChR subunits are there?
4.
Which ions are nAChRs permeable to?
Sodium.
Potassium.
Certain subunit combinations confer calcium permeability too.
Describe the structure of nAChRs.
5 transmembrane spanning subunits couple together to form the ion channel complex.
Each subunit consists of four membrane-spanning alpha helices.
Can be homomeric or heteromeric.
Describe how functional nAChRs are widely distributed.
Distributed across:
Different neuron types.
Different brain regions.
Differentially localised within a neuron, on the soma, dendrites or synaptic terminals.
What does the diverse distribution of nAChRs suggest?
Modulation of plasticity and activity at a network level more than linear regulation of individual synaptic pathways.
How do nAChRs modulate NT release?
nAChRs are present on the presynaptic terminals of other NT systems.
What is the importance of homomeric alpha-7 nAChR signalling?
Can enhance induction of LTP in the hippocampus.
Promotes maturation and survival of adult-born neurons.
Transform GABAergic currents from excitatory in early development to inhibitory later in development.
What do defects in cholinergic signalling cause?
Impairments in learning and memory.
Which two types of synapses most often contain nAChRs?
Glutamatergic or GABAergic.
What type of receptor are muscarinic ACh recpetors (mAChRs)?
GPCR.
Name the five subtypes of mAChRs.
M1-M5.
What is atropine?
A competitive and reversible antagonist of mAChRs.
What is the main role of mAChRs?
Mediate the neuroeffector junction of the PNS.
Which mAChR subtypes are highly expressed in the brain?
M1, M2 and M4.
Which G-protein couples to M1, M3 and M5 mAChRs?
Gq.
Which G-protein couples to M2 and M4 mAChRs?
Gi/o.
Describe the mechanism of action for M1, M3 and M5 mAChRs.
Activates phospholipase C, IP3 and DAG.
Increases calcium ion conductance.
Upregulates MAP kinases.
Describe the mechanism of action for M2 and M4 mAChRs.
Inhibits adenylyl cyclase to reduce levels of cAMP.
Downregulates MAP kinases.
Decreases calcium ion conductance.
Describe the two main roles of M1 mAChRs.
Gut motility and gastric secretions.
Attenuate potassium conductance to produce excitatory effects at the ganglia.
Why does an M2 mAChR produce mainly inhibitory effects?
Produces an increase in potassium and a decrease in calcium conductance.
What is the role of M2 mAChR in the heart?
Reduces heart rate and contraction due to closure of calcium channels.
Which three roles are M3 mAChRs involved in?
Contribute to smooth muscle contraction in the gastrointestinal and urinary tracts.
Role in bronchoconstriction and vasodilation.
Help to stimulate glandular secretions.
Explain the process of second messenger systems.
NT binds to the receptor and activates the G-protein.
G-protein subunit activates phospholipase C (PLC).
PLC splits PIP2 into IP3 and DAG.
DAG activates protein kinase C (PKC).
IP3 binds to IP3 receptors on calcium channels in the membrane of the SER.
Which pathway is an important source of intracellular calcium ions?
PIP2-IP3 pathway.
Explain how intracellular calcium ions activate protein kinases.
Calcium binds to calmodulin in the cytosol.
The calcium-calmodulin complex binds to the regulatory subunit of the calcium-calmodulin dependent protein kinase (CaMK).
The catalytic subunit of CaMK is exposed, activating the kinase.
What are the two components of the stress response?
Autonomic.
Neuroendocrine.
Which molecule mediates the autonomic stress response?
Adrenaline.
Which molecule mediates the neuroendocrine stress response?
Cortisol.
List three symptoms of the autonomic stress response.
Increased heart rate and breathing.
Heightened senses and alertness.
Focused attention.
List three symptoms of the neuroendocrine stress response.
Increase in blood glucose.
Suppressed immune function.
Stops digestion.
What is the role of the ANS?
It regulates the viscera of the body, e.g. secretions of certain glands, heart rate, and peristalsis.
Define peristalsis.
Contraction of smooth muscle in the digestive tract.
Which subsection of the ANS is involved in the autonomic stress response?
SNS.
Which subsection of the ANS is involved in the neuroendocrine stress response?
PNS.
Describe the process of ACh release in the SNS.
Most preganglionic neurons originate in the spinal cord.
Their short axons release ACh onto postganglionic neurons and activate them.
Postganglionic neurons release NA onto target organs.
Describe the process of ACh release in the PNS.
The cell bodies of preganglionic neurons are located in the brainstem and sacral spinal cord.
Their long axons release ACh onto postganglionic neurons and activate them.
Postganglionic neurons are located near target organs, so they release ACh onto target organs.
Describe the mechanism of action of nicotine in the SNS.
Stimulates NA release by activating mAChRs localised on peripheral postganglionic neurons.
Increases heart rate and blood pressure.
Define the neuromuscular junction (NMJ).
A specialised site that connects the terminal of a motor neuron axon to skeletal muscle.
How are muscle fibres innervated?
Each muscle fibre is innervated and controlled by a single motor neuron.
Where is the motor neuron cell body located?
Within the spinal cord.
What is the motor end plate?
The site where a motor neuron axon synapses with a muscle fibre.
Where does ACh bind to once it has been released from the presynaptic motor neuron?
Postsynaptic nAChRs concentrated in the folded membrane at the motor end plate.
Via which process is ACh released from the presynaptic motor neuron terminal?
Calcium-dependent exocytosis.
What is the role of the junctional folds in the motor end plate?
Allows ACh to accumulate to depolarise the membrane (sarcolemma) of the muscle fibre.
How do neurotoxins inhibit ACh release?
They interfere with the SNARE proteins that mediate vesicle fusion.
This prevents fusion of synaptic vesicles with the presynaptic membrane, thereby inhibiting exocytosis.
What is the cause of myasthenia gravis?
Autoantibodies block nAChRs at the NMJ, leading to reduced muscle contraction.
Define myasthenia gravis.
It is an autoimmune disorder characterised by weakness of skeletal muscles.
