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NEUR531 > Topic 4: Neurotransmitters > Flashcards

Topic 4: Neurotransmitters Flashcards

1
Q

What are the 3 major classes of neurotransmitters? and what is the exception?

A

-amino acids
-amines (derived from amino acids)
-peptides (constructed from amino acids)
(ACh is exception, derived from actylel CoA and choline )

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2
Q

What is the criteria of a molecule to be deemed a neurotransmitter?

A
  1. The molecule must be synthesized and stored in the presynaptic neuron
  2. the molecule must be released by the presynaptic axon terminal upon stimulation
  3. the molecule, when experimentally applied, must produce a response in the postsynaptic cell that mimics the response produced by the release of neurotransmitter from the presynaptic neuron
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3
Q

What is immunocytochemistry used for and what is it called when the same technique is applied to thin sections of tissue, including brain?

A

-used to anatomically localise particular molecules to particular cells –> used to localise any molecule for which a specific antibody can be generated, including synthesizing enzymes for transmitter candidates
-when used for thin sections of tissues including brain its referred to as immunohistochemistry.

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4
Q

What is the method behind using immunohistochemistry in identifying a transmitter?

A

-once transmitter candidate has been chemically purified, it is injected under the skin or into the bloodstream of animal where it stimulates an immune response
-one feature of the immune response is the generation of large proteins called antibodies
-antibodies can bind tightly to specific site on foreign molecule aka the antigen, in this case the transmitter candidate
- these specific antibody molecules can be recovered from a blood sample of the immunized animal and chemically tagged with a colourful marker, so can be seen with microscope
-when these labelled antibodies are applied to a section of brain tissue, they will colour just those cells that contain transmitter candidate
-by using several different antibodies, each labelled with different marker colour, it is possible to distinguish several types of cells in the same region of the brain

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5
Q

what is the use of immunocytochemistry being able to localise synthesising enzymes for transmitter candidates as well as any molecule for which antibody can be generated?

A

demonstrates that the transmitter candidate and its synthesizing enzyme are contained in the same neuron - or same axon terminal - which can help satisfy the criterion that the molecule is localised in and synthesised by a particular neuron

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6
Q

What is the method in situ hybridization useful for?

A

-confirming that a cell synthesizes a particular protein or peptide
-method for localizing specific mRNA transcripts for proteins

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7
Q

How does in situ hybridization work and the underlying mechanism behind it?

A

-There is unique mRNA molecule for every polypeptide synthesized by neuron –> mRNA transcript has 4 different nucleic acids linked together in various sequences to form a long strand
-Nucleic acid bind most tightly to complementary nucleic acid
-If sequence is nucleic acid in strand is known –> construct complementary strand (called a probe) that will stick like Velcro to mRNA molecule
-Process that probe bonds to mRNA called hybridization
- Chemically label the probe so it can stick to any complementary mRNA strands, then wash away all the extra probes that have not stuck, finally we search for neurons that contain the label.

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8
Q

what are the ways the probes in in situ hybridization chemically tagged?

A

-make them radioactive, detected by laying brain tissue on sheet of special film sensitive to radioactive emissions, visible as white dots. Digital electronic imaging devices can be used to detect radioactivity –> called autoradiography
-another method, label with brightly coloured fluorescent molecules –> can be viewed directly with microscope –> fluorescent in situ hybridization is aka FISH

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9
Q

Which approach helped Loewi and Dale identify ACh as transmitter at many peripheral synapses?

A

-In some cases, a specific set of cells or axons can be stimulated while taking samples of the fluids bathing their synaptic targets. The biological activity of the sample can then be tested to see if it mimics the effect of the intact synapses, and then the sample can be chemically analysed to reveal the structure of the active molecule.

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10
Q

One way to collect the chemicals release by CNS is to use brain slices that are kept alive in vitro… explain this

A

To stimulate release, the slices are bathed in a solution containing a high K + concentration. This treatment causes a large membrane depolarization, thereby stimulating transmitter release from the axon terminals in the tissue. Because transmitter release requires entry of Ca 2+ into axon terminal, it must also be shown that the release of the neurotransmitter candidate from the tissue slice after depolarization occurs only when Ca 2+ ions are present in the bathing solution.

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11
Q

What method enables activation of just one specific types of synapse at a time? and how is it done?

A

optogenetics, genetic methods are used to induce one particular population of neurons to express light-sensitive proteins, and then those neurons can be stimulated with brief flashes of light that have no effect on the surrounding cells. Any transmitters released are likely to have come from the optogenetically selected type of synapse.

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12
Q

Even when it has been shown that a transmitter candidate is released upon depolarization in a calcium-dependent manner, can we be sure that the molecules collected in the fluids was released from the axons terminals, why/why not?

A

No, because they may have been released as a secondary consequence of synaptic activation. These technical difficulties make the second criterion— that a transmitter candidate must be released by the presynaptic axon terminal upon stimulation— the most difficult to satisfy unequivocally in the CNS.

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13
Q

What is the microiontophoresis method used for?

A

To assess the postsynaptic actions of a transmitter candidate

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14
Q

Describe the microiontophoresis method

A

-Neurotransmitter candidate –>dissolved in solutions –>acquire a net electrical charge.
-A glass pipette with a very fine tip (few micrometres), filled with ionized solution. The tip of the pipette positioned next to postsynaptic membrane of neuron; transmitter candidate ejected in very small amounts by passing electrical current through the pipette.
-Neurotransmitter candidates can also be ejected from fine pipettes with pulses of high pressure. A microelectrode in the postsynaptic neuron can be used to measure the effects of the transmitter candidate on the membrane potential.

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15
Q

What happens if iontophoretic or pressure application from microiontophoresis causes electrophysiological changes that mimic effects of transmitter and the other criteria of localisation, synthesis and release are met?

A

Then the molecule and the transmitter are usually considered to be the same chemical

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16
Q

as a rule, no 2 neurotransmitters bind to the same…

A

receptor, however one neurotransmitter can bind to many different receptors

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17
Q

What are the 3 methods that are particularly useful in studying different receptor subtypes?

A

-neuropharmacological analysis of synaptic transmission
-ligand-binding methods
-molecular analysis of receptor proteins

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18
Q

What is an example of neuropharmacological analysis discovering receptor subtypes?

A

ACh receptors –nicotine receptor agonist in skeletal muscle no responses in heart, muscarine agonist in heart, no response in skeletal muscle.
–>curare antagonist to ACh nicotinic receptors, atropine antagonist to muscarine receptor

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19
Q

how many subtypes for glutamate receptors and describe them

A

AMPA, NMDA and kainate receptors

-glutamate activates all three
-AMPA only acts on AMPA receptors
-NMDA only acts on NMDA receptor
-Kainate only acts on Kainate receptor

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20
Q

What is Noradrenaline and GABA subtypes?

A

noradrenaline - alpha and beta receptor
GABA - GABAa and GABAb

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21
Q

What is the ligand binding method?

A

The technique of studying receptors using radioactively or nonradioactively labelled ligands is called the ligand binding method. Notice that a ligand for a receptor can be an agonist, an antagonist, or the chemical neurotransmitter itself. Specific ligands were invaluable for isolating neurotransmitter receptors and determining their chemical structure. Ligand-binding methods have been enormously important for mapping the anatomical distribution of different neurotransmitter receptors in the brain.

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22
Q

What is a ligand?

A

Any chemical compound that binds to a specific site on a receptor is called a ligand for that receptor

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23
Q

what are the 2 groups of receptors proteins?

A

-transmitter-gated ion channels
-G-protein-coupled (metabotropic) receptors

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24
Q

What is Dale’s principle?

A

that a neuron has only one neurotransmitter –> many peptide-containing neurons violate Dale’s principle

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25
Q

What are co-transmitters?

A

When 2 or more transmitters are releases from one nerve terminal these are co-transmitters – e.g., glycine and GABA

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26
Q

What specific enzyme does ACh require for making it? and where is it manufactured?

A

choline acetyltransferase (ChAT), manufactured in soma and transported to axon terminal –> only cholinergic neurons contain ChAT –> transfers an acetyl group from acetyl CoA to choline (from extracellular fluid)

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27
Q

what is the role of the ACh transporter?

A

Neurotransmitter is concentrated in synaptic vesicles by the actions of a vesicular ACh transporter

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28
Q

What is the rate-limiting step in ACh synthesis?

A

the transport of choline into the neuron

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29
Q

What is AChE?

A

acetylcholinesterase, degradative enzyme, secreted in cleft, degrades ACh into choline and acetic acid

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30
Q

What is the amino acid tyrosine a precursor to?

A

structures called catecholamines
-dopamine
-noradrenaline
-adrenaline

31
Q

What is tyrosine hydroxylase (TH)

A

contained in all catecholaminergic neurons –> first step in catecholamine synthesis, the synthesis of tyrosine to dopa
-TH is rate limiting for catecholamine synthesis

32
Q

What is the precursor to dopamine and what does it use to convert into DA?

A

Dopa, uses enzyme dopa decarboxylase to convert dopa into DA

33
Q

What is the precursor to noradrenaline and what does it use to convert into noradrenaline?

A

Dopamine, uses enzyme called dopamine beta-hydroxylase (DBH)
- created in synaptic vesicles

34
Q

What is the precursor to adrenaline and what does it use to covert it into adrenaline?

A

noradrenaline, uses enzyme phentolamine N-methyltransferase (PNMT)
- synthesised in cytosol, NA made in vesicles and released in cytosol to convert into adrenaline

35
Q

How are catecholamines removed from cleft?

A

selective reuptake back into axon terminal via Na+ dependent transporters

36
Q

What happens after uptake of catecholamines?

A

Can be reused or broken down by action of monoamine oxidase (MAO) –> found on outer membrane of mitochondria

37
Q

Describe serotonin (5-HT)

A

-amine
-derived from amino acid tryptophan
-relatively few serotoninergic neurons
-important for regulation of mood, emotional behaviour and sleep

38
Q

describe the synthesis of serotonin.

A

-first step, tryptophan converted into 5-hydroxytryptophan (5-HTP) by enzyme tryptophan hydroxylase
-second step, 5-HTP converted to 5-HT by enzyme 5-HTP decarboxylase
-limited by availability of tryptophan

39
Q

how is 5-HT remove from cleft? and then what?

A

by reuptake by transporter –> can be reused or broken down by MAO

40
Q

What are the main amino acids that serves as neurotransmitters?

A

-glutamate (Glu)
-glycine (Gly)
-gamma-aminobutyric acid (GABA)

41
Q

What are glutamate and glycine synthesised from?

A

glucose and other precursors by actions of enzymes that exist in cells

42
Q

What is GABA derived from?

A

glutamate, key synthesizing enzyme is glutamic acid decarboxylase (GAD)

43
Q

how are the amino acid transmitters removed from cleft? and then what?

A

selective reuptake into presynaptic terminals and glia, by Na+ dependent transporters, then GABA is metabolized by enzyme GABA transaminase

44
Q

What is adenosine triphosphate (ATP)?

A

-key molecule in cellular metabolism – also transmitter
- directly excites neurons by gating cation channels
-binds to purinergic receptors
-following release from synapses, ATP degraded by extracellular enzyme yielding adenosine

45
Q

What are endocannabinoids (endogenous cannabinoids)?

A

-small lipid molecules
-released from postsynaptic and act on presynaptic terminals
-this communication called retrograde signalling thus they are retrograde messengers
-serve as feedback system to regulate conventional forms of transmission

46
Q

describe the structure of nicotinic ACh channel at neuromuscular junction

A

-pentamer, amalgam of five protein subunits arranged like staves of barrel to form a single pore through membrane
-4 different types of polypeptides are used as subunits for the nicotinic receptor, α, β, γ, and δ
-mature channel is made form α2βγδ (2 alpha one of each of others)
-one binding site to each alpha subunit –> simultaneous binding of ACh to both sides are required for channel to open

47
Q

describe the structure of nicotinic ACh receptor on neuron

A

-pentamer, made up of α3β2

48
Q

What does the nicotinic ACh, GABAa and glycine receptor have in common?

A

all pentameric complexes of subunits

49
Q

describe the glutamate channel

A

-tetramer (4)
-M2 region does not span the membrane, instead hairpin that both enters and exits from inside membrane

50
Q

describe amino-acid gated channels

A

-mediate most fast synaptic transmission in CNS

-several properties distinguish them from one another and define their functions within brain
–The pharmacology of their binding sites describes which transmitters affect them and how drugs interact with them.
–The kinetics of the transmitter binding process and channel gating determine the duration of their effect.
–The selectivity of the ion channels determines whether they produce excitation or inhibition and whether Ca 2+ enters the cell in significant amounts.
–The conductance of open channels helps determine the magnitude of their effects

all of these properties are direct result of molecular structure of channels

51
Q

which glutamate subtypes mediates bulk of brains fast excitatory transmission?

A

AMPA- and NMDA-gated channels –> kainate receptors not fully understood

52
Q

What are AMPA-gated channels permeable to?

A

Na+ and K+, most not permeable to Ca2+

53
Q

how do NMDA-gated channels differ from AMPA?

A

(1) NMDA-gated channels are permeable to Ca 2+
(2) inward ionic current through NMDA-gated channels is voltage dependent

54
Q

What happens when NMDA-gated channels open?

A

-Ca 2+ and Na + enter the cell (and K + leaves)
-at normal negative resting membrane potentials, the channel becomes clogged by Mg 2+ ions, and this “magnesium block” prevents other ions from passing freely through the NMDA channel. –Mg 2+ pops out when the membrane is depolarized, which usually follows the activation of AMPA channels at the same and neighbouring synapses.
-Both glutamate and depolarization must coincide before the channel will pass current. This property has a significant impact on synaptic integration at many locations in the CNS.

55
Q

What mediates most inhibition in CNS?

A

GABA mediates most, glycine mediates most of the rest

56
Q

What do GABAa and glycine receptor gate?

A

a chloride channel

57
Q

What do benzodiazepines and barbiturates do?

A

when GABA is present benzodiazepines increase frequency of channel opening and barbiturates increase duration of channel opening

58
Q

What are the steps of G-protein couple receptors action?

A

(1) binding of the neurotransmitter to the receptor protein,
(2) activation of G-proteins
(3) activation of effector systems

59
Q

what is the structure of G-protein couple receptors?

A

-consist of a single polypeptide containing seven membrane-spanning alpha helices.
-Two of the extracellular loops of the polypeptide form the transmitter binding sites. Structural variations in this region determine which neurotransmitters, agonists, and antagonists bind to the receptor.
-Two of the intracellular loops can bind to and activate G-proteins. Structural variations here determine which G-proteins and, consequently, which effector systems are activated in response to transmitter binding.

60
Q

Describe the G-protein mode of operation

A
  1. Each G-protein has three subunits, termed α, β, and γ. In the resting state, a guanosine diphosphate (GDP) molecule is bound to the Gα subunit, and the whole complex floats around on the inner surface of the membrane.
  2. If this GDP-bound G-protein bumps into the proper type of receptor and if that receptor has a transmitter molecule bound to it, then the G-protein releases its GDP and exchanges it for a GTP that it picks up from the cytosol.
  3. The activated GTP-bound G-protein splits into two parts: the Gα subunit plus GTP and the Gβγ complex. Both can then move on to influence various effector proteins.
  4. The Gα subunit is itself an enzyme that eventually breaks down GTP into GDP. Therefore, Gα eventually terminates its own activity by converting the bound GTP to GDP
  5. The Gα and Gβγ subunits come back together, allowing the cycle to begin again
61
Q

What is the subdivisions of G-proteins?

A

Gs stimulatory and Gi inhibitory

62
Q

What are the 2 types of ways G-proteins exert their effect?

A

-binding to G-protein-gated ion channels and to G-protein-activated enzymes (second messenger cascades)
-G-protein-gated ion channel binding aka shortcut pathway because doesn’t involved other chemical intermediaries (or membrane-delimited pathway)

63
Q

Describe the G-protein-gated ion channels (aka the shortcut pathway)

A

-βγ subunits migrate laterally along the membrane until they bind to the right type of potassium channel and induce it to open.
-30-100 msec for responses
-localised, cannot move very far, thereby only close channels can affect it
-referred to as membrane-delimited pathway because all action occurs within membrane
-(e.g., muscarinic receptors in heart take shortcut pathway)

64
Q

Describe the second messenger cascades

A

-trigger elaborate series of biochemical reactions, often ends in activation of other “downstream” enzyme that alter neural function
-between first enzyme and last there are several second messengers –> this process called second messenger cascades`

65
Q

describe the noradrenaline β receptor and cAMP

A

-cAMP second messenger cascade initiated by activation of noradrenaline β receptors
- begins with β receptor activating the stimulatory G-protein, Gs, which proceeds to stimulate the membrane bound enzyme adenylyl cyclase.
-Adenylyl cyclase converts ATP to cAMP. The subsequent rise of cAMP in the cytosol activates a specific downstream enzyme called protein kinase A (PKA).

66
Q

what is the push-pull method and how is it used in cAMP inhibition?

A

-means one to stimulate and one to inhibit
-activation of the second type of noradrenaline receptor called alpha-2 receptor, leads to activation of Gi (inhibitory G-protein). Gi suppresses the activity of adenylyl cyclase (converts ATP to cAMP), and this effect can take precedence over the stimulatory system

67
Q

describe how activation of various G-proteins can cascades branches

A

-Activation of various G-proteins can stimulate phospholipase C (PLC), an enzyme that floats in the membrane-like adenylyl cyclase.
-PLC acts on a membrane phospholipid, splitting it to form two molecules that serve as second messengers: diacylglycerol (DAG) and inositol-1,4,5triphosphate (IP3).
-DAG, a lipid-soluble, stays within the plane of the membrane where it activates a downstream enzyme, protein kinase C (PKC).
-At the same time, the water-soluble IP3 diffuses away in the cytosol and binds to specific receptors on the smooth ER and other membrane-enclosed organelles in the cell.
-These receptors are IP-3 -gated calcium channels, so IP-3 causes the organelles to discharge their stores of Ca 2+.

68
Q

What can elevations in cytosolic Ca2+ trigger?

A

widespread and long-lasting effects. one effect is the activation of the enzyme calcium-calmodulin-dependent protein kinase (CaMK)

69
Q

What is phosphorylation?

A

The process of protein kinases transferring phosphate from ATP floating in cytosol to proteins

70
Q

Consider example of Beta type of noradrenaline receptors on cardiac muscle in terms of subsequent rise in cAMP, describe it

A

rise in cAMP activates PKA, which phosphorylates the cell’s voltage-gated calcium channels, this enhances activity, more Ca2+ flows and heart beats stronger

71
Q

What do protein phosphatases do?

A

act rapidly to remove phosphate groups. The degree of channel phosphorylation at any moment therefore depends on the dynamic balance of phosphorylation by kinases and dephosphorylation by phosphatases.

72
Q

what are the advantages of G-protein-coupled receptors?

A

-signal amplification, activation of one can lead to activation of many ion channels
-signal over distance
-sites for further regulation
-generate long-lasting chemical changes in cells

73
Q

what is divergence?

A

ability for one transmitter to activate more than one subtype of receptor and cause more than one type of postsynaptic response

74
Q

What is convergence?

A

multiple transmitters each activating their own receptor type, can converge to influence the same effector system

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