Chemical Neurotransmitters Flashcards
Define synapse
A specialised junction between the axon terminal and post synaptic cell
What are the two types of synapses?
Electrical synapse
Chemical synapse
Why is synaptic transmission important?
Synaptic transmission is important to understand how the nervous system operates the following:
- cognition, learning & memory
- actions of psychoactive drugs
- causes of psychiatric and neurological disorders
What is a gap junction composed of?
6 connexins (gap junction protein) which make a connexon. The pore size is 2nm
What is an electrical synapse? Expand on its transmission and where it is found. (7 points)
- It allows the direct transfer of ionic current from one cell to the next.
- Gap junctions are composed of 6 connexins; that make up 1 connexon. The pore size is 2nm.
- Ions can flow bidirectionally.
- The cells are said to be electrically coupled.
- The conduction speed is very fast (0.3milliseconds) unlike the delay seen in chemical transmission.
- It is found in neuronal pathways that are associated with escape reflexes (fight or flight –> amygdala) or in neurones that need to be synchronised (cardiomyocytes that make up the heart muscle - you want the propagation of the action potential to proceed smoothly and uninterrupted from one cell to another to provide a uniform contraction of the heart)
- they are common in non-neuronal cells (glial cells - maintain homeostasis, form myelin)
Explain the information flow through neurones
Dendrites collect electrical signals.
Cell body integrates incoming signals and generates an outgoing signal to axon (through axon hillock)
Axon passes electrical signals to dendrites of another cell or to an effector cell
Define neuropharmacology
The study of the drugs on the nervous system
How are neurological and psychiatric disorders often caused by?
An imbalance of chemical transmitters in the brain
How can chemical synaptic transmission be modulated?
Drugs and Toxins
What do receptor agonists do?
They mimic the action of a neurotransmitter e.g. Morphine activates u-opioid receptors in the brain and spinal cord
What do receptor antagonists do?
They inhibit the normal action of a neurotransmitter e.g. ketamine blocks the action of glutamate at the NMDA receptor
Excitatory receptor + agonist = ____ signal
MORE
Inhibitory receptor + antagonist = ____ signal
MORE
Excitatory receptor + antagonist = ____ signal
LESS
Inhibitory receptor + agonist = ____ signal
LESS
What is an axon hillock?
The part of the neurone where the cell body meets the axon
What is the resting membrane potential and what is this due to?
-70mV - this is due to the concentration of ions (+vely or -vely charged particles) inside and outside the cell
What is on the outside of the cell?
High concentration of +vely charged Na ions and some -vely charged Cl ions
What is on the inside of the cell?
Low concentration of +vely charged K ions and high concentration of -vely charged protein ions
If enough +vely charged ions enter the cell, thereby resulting in more excitatory post synaptic potentials. Then the membrane potential reaches a threshold of excitation at the axon hillock. This will trigger an action potential. What is an action potential?
A brief increase in the permeability of the membrane to Na+ (in), immediately followed by a brief increase in the permeability of the membrane to K+ (out). Once an action potential is generated, it propagates all the way down to axon to the terminal buttons. While EPSP’s are small, local and contained graded changes in the membrane potential from more -ve to more +ve, an AP is a brief but larger reversal in the membrane polarity. Once the AP reaches the terminal buttons this change in membrane polarity causes Ca channels which are normally held closed to open, and let Ca into the cell. Ca acts as a signal to release the neurotransmitter substance which is docked at the presynaptic membrane via exocytosis. The neurotransmitter then binds to the post-synaptic receptor and the cycle begins again.
Neurotransmitters are released in _____
quanta
Summarise synaptic signal integration
Neurotransmitters are released in quanta. Each neurone can receive thousands of inputs in the form of ion channel and G protein-coupled receptor activation.
EPSP Summation:
Neurones perform sophisticated computation by adding together EPSPs to produce a significant post synaptic depolarisation.
Types of Summation: Spatial and Temporal summation
These complex inputs give rise to discrete outputs in the form of action potentials a.k.a neural computation.
What are the two types of EPSP summation?
Spatial
Temporal
Name two excitatory neurotransmitters (Na+ enters):
ACh
Glutamate
What will a single presynaptic action potential give rise to?
a small EPSP in a post synaptic neuron
What is and what will SPATIAL summation of EPSPs give rise to?
When two or more presynaptic inputs are active at the same time, their individual EPSPs are added together. It is better than TEMPORAL because it is quicker in generating an AP
What is and what will TEMPORAL summation of EPSPs give rise to?
When the same presynaptic input fibre fired APs in quick succession, the individual EPSPs add together. Not as good as SPATIAL because it takes longer to generate an AP.
Name two inhibitory neurotransmitters (Cl- enters):
Glycine
GABA
What glial cells are present in the CNS to myelinate the axons there?
Oligodendrocytes
What glial cells are present in the PNS to myelinate the axons there?
Schwann cells
Where in the neurone does summation occur?
Axon hillock
What drug is given to treat MS?
Fingolimod
What is Desipramine?
Tricyclic antidepressant. Inhibits reuptake of norepinephrine.
What is Clonidine?
For ADHD, anxiety, migraine, drug withdrawal.
What chemical neurotransmitters are involved in memory?
Lack of, will cause:
- Ach
- Amino acids e.g. glutamate, GABA
- ALZHEIMER’S
What chemical neurotransmitters are involved in cognition, movement?
Lack of, will cause:
- Catecholamines e.g Dopamine, noradrenaline
- SCHIZOPHRENIA/ PARKINSONS
What chemical neurotransmitters are involved in sleep, mood, appetite?
Lack of, will cause:
- Indoleamine e.g. Serotonin
- DEPRESSION/ ANXIETY
What chemical neurotransmitters are involved in pain?
Lack of, will cause:
- Peptides e.g. opioids
- ANALGESIA
Is Ach inhibitory or excitatory?
excitatory
Is GABA inhibitory or excitatory?
inhibitory
Is glutamate inhibitory or excitatory?
excitatory
Is 5-HT inhibitory or excitatory?
excitatory
Is histamine inhibitory or excitatory?
excitatory
Is glycine inhibitory or excitatory?
inhibitory
Properties of neurotransmitters:
- synthesised within the neurone
- packaged and stored in vesicles
- The substance is released in response to presynaptic depolarisation
- The release is dependent on the influx of Ca++ in the presynaptic terminal
- There must be specific receptors for the substance on the post synaptic terminal
- Both the endogenous and exogenous transmitter must elicit the same response (within a physiological concentration range)
- There will usually be a mechanism present to remove the transmitter from the synaptic cleft i.e. presence of a deactivation mechanism
What are autoreceptors?
They are sometimes found on the presynaptic terminal.
Activation can lead to:
- inhibition of neurotransmitter release or
- neurotransmitter synthesis
(negative feedback)
They may act as a brake on the release of neurotransmitters
Why should neurotransmitters be cleared from the synapse?
to permit another round of synaptic transmission
How can neurotransmitters be cleared?
- Diffusion
- Re-uptake by presynaptic terminal followed by recycling or degradation
- Uptake by glia cells
- Post synaptic uptake and desensitisation
- Enzyme degradation in the synapse
Name some mechanisms of agonist drug action:
- increase the synthesis of neurotransmitter (by increasing the amount of precursor)
- increase the number of neurotransmitter by destroying degrading enzymes
- increase the release of neurotransmitter molecules from terminal buttons
- binds to autoreceptors and blocks their inhibitory effect on neurotransmitter release
- blocks deactivation of neurotransmitter by blocking degradation or re-uptake
- binds to postsynaptic receptors and either activates them or increases effect of them on neurotransmitter
Name some mechanisms of antagonist drug action:
- block the synthesis of neurotransmitter (by destroying synthesising enzymes)
- cause the neurotransmitter molecules to leak from the vesicles and be destroyed by degrading enzymes
- block the release of neurotransmitter molecules from terminal buttons
- activate autoreceptors and inhibits neurotransmitter release
- drug is a receptor blocker binds to postsynaptic receptors and blocks effect of neurotransmitter
What are ligand-gated ion channels and how do they work?
Transmembrane channel protein with a ligand binding domain. The channel opens once a neurotransmitter binds. Activation is generally rapid and is mediated by amino acids and amines.
Change in membrane potential depends on the specific ions that pass through the pore:
Na+ and K+ channels cause depolarisation and are excitatory.
Cl- channels cause hyperpolarisation and are inhibitory
What are ligand gated ion channels mediated by?
Amino acids and amines
G protein-coupled receptor structure:
Receptor with ligand binding domain connected to G protein consisting of alpha, beta and gamma subunit.
Activation of G protein-coupled receptor?
1 - Ligand binds to receptor
2 - G protein becomes activated
3 - G protein dissociates
4 - Alpha subunit activates an effector protein
G- protein effectors: G proteins act in one of two ways:
- open ion channels
- activate enzymes that synthesis second-messenger molecules.
Compare ligand gated and G protein- coupled receptors
G protein coupled receptors tend to be slower, longer lasting and have greater diversity than ligand-gated ion channels.
Explain how Ach is broken down/made.
Ach = Acetyl CoA + Choline
Ach is rapidly broken down in the synaptic cleft by acetylcholinesterase
Choline is transported back to the axon terminal and is used to make more Ach.
Which steps allow amplification of secondary messenger
Receptor (amp) → G protein → Adenylyl cyclase (amp) → cyclic AMP → Protein Kinase (amp)→ phosphate is added to the target protein
There are two outcomes of G coupled protein receptors:
1 - ion channel opens OR
2- activates an enzyme that synthesises secondary proteins.This causes a cascade of biological events inside the cell such as: change in calcium concentration, open/closing channels, change gene transcription, change protein translation.
Acetylcholine acts on which two receptors?
- Muscarinic - G protein coupled receptor
- Nicotinic - ligand gated ion channel
Name the type and location of receptor:
Where is M1 found?
Where is M2 found?
Where is M3 found?
Neural - therefore CNS
Cardiac - therefore Atria
Glandular - therefore Smooth muscle
Name an:
Agonist for muscarinic receptors?
Antagonist for muscarinic receptors?
– Ach/ Carbochol (CCh)
– Atropine
What enzyme converts Tyrosine to DOPA?
Tyrosine Hydroxylase (TH)
What enzyme converts DOPA to dopamine?
Dopa decarboxylase
Which of the two enzymes is a rate-limiting enzyme?
TH
Tyrosine to Dopamine is the slowest reaction in the pathway because it is the
rate limiting step
What enzyme converts Tryptophan to 5-HTP?
What enzyme converts 5-HTP to Serotonin?
Tryptophan hydroxylase
5-HTP decarboxylase
What are the four pathways for dopamine? Expand on each one.
Nigro-striatal pathway has to do with movement
Meso-Limbic pathway is also known as the ‘reward’ pathway. What symptoms of schizophrenia rise from this pathway? Give examples. – positive symptoms (psychosis; hallucinations, delusions, disordered speech → extra feelings or behaviours that are not present
Meso-cortical pathway is involved in motivation & emotions. What symptoms of schizophrenia rise from this pathway? Give examples. → negative symptoms (blunted emotions, lack of motivation, inability to experience pleasure)
Tubulo-infundibular pathway is present in the prosterior pituitary.
Nicotine receptor is made of _ alpha, _ beta and _ gamma subunit. Ach binds to ____ subunit and causes and influx of Ca++ – > depolarisation
2
2
1
alpha
What kind of drug is Prozac (Fluoxetine)
Selective Serotonine Reuptake Inhibitor
How do you make norepinephrine from dopamine?
Dopmamine beta hydroxylase
How do MAOIs work?
- Presynaptic neurone releases serotonin into synaptic cleft so that it can be taken up by the post synaptic neurone
- Sometimes, molecules such as MAOs, degrade the serotonin that is present in the synaptic cleft.
- This reduces the amount of serotonin that makes it into the post synaptic neurone and thus can cause DEPRESSION due to LOW CONCENTRATION OF SEROTONIN
- In order to overcome this, we can use drugs such as Prozac. This is a MAO INHIBITOR.
- Thus, this will bind to the MAO and deactivate it.
- The MAO can no longer degrade the serotonin and so serotonin can continue making its way to the post synaptic neurone where it is taken up.
Is glutamate inhibitor or excitatory? What is it involved in?
It is released by 80% of brain neurons. It is an excitatory neurotransmitter. It is involved in memory, learning and cognition.
What neurotransmitters act on the NMDA receptor?
Glycine and glutamate
What is long-term potentiation?
Long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons.
What enzyme converts glutamine to glutamate?
Glutaminase
What enzyme converts glutamate to GABA?
Cytosolic glutamic acid decarboxylase
GABA receptors consist of _____ and _____ subunits
alpha
gamma
