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Cell and Molecular Neuroscience > Bortolato > Flashcards

Bortolato Flashcards

1
Q

What pathways enable electrical synapses to function?

A

Gap juctions

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2
Q

In what tissues are gap junctions found?

A

Cardiac Muscle, some types of smooth muscle

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3
Q

In which direction do NTs move across synaptic cleft?

A

Unidirectional, always from presynaptic cell to postsynaptic cell

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4
Q

Define Spatial Summation

A

occurs when two or more presynaptic inputs arrive at a postsynaptic cell simultaneously.

If both inputs are excitatory, they will combine to produce greater depolarization than either input would produce separately.

If one input is excitatory and the
other is inhibitory, they will
cancel each other out.

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5
Q

Define Temporal Summation :

A

occurs when two presynaptic inputs
arrive at the postsynaptic cell
in rapid succession. Because
the inputs overlap in time, they
summate.

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6
Q

Criteria for neurotransmitter status

A

The chemical must be produced and found within a neuron.
The chemical is released upon neuronal stimulation
Blocking the receptor blocks the biological effect.
If the chemical is applied artificially, it should have the same
effect as when it is released by a neuron.
When a chemical is released, it must act on a receptor and
cause a biological effect.
After a chemical is released, it must be inactivated.

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7
Q

The following four criteria are used to formally designate
a substance as a classical neurotransmitter:

A
  1. The substance must be synthesized and stored in the
    presynaptic axon terminal (synaptic bouton);
  2. The substance must be released by the synaptic
    bouton upon stimulation;
  3. If the substance is administered exogenously to the
    postsynaptic membrane at physiologic concentration,
    the response of the postsynaptic cell must mimic the in
    vivo response;
  4. A specific reuptake and catabolic mechanism must
    exist for removing the substance from its site of action.
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8
Q

Key steps of classical neurotransmission

A

The major processes in chemical
neurotransmission:
double S, triple R
Synthesis
Storage
Release
Receptor activation
Removal/Reuptake
* These processes are regulated
physiologically.
* Drugs affect these processes.

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9
Q

synaptic fatigue

A

defined as a smaller than
expected response in the postsynaptic cell, possibly resulting from the
depletion of neurotransmitter stores from the presynaptic terminal.

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10
Q

Presynaptic receptors

A

The basic concept: release of neurotransmitters can
be strongly influenced (+ or -) by chemical messengers
in the immediate microenvironment, acting on their
own receptors on other nerve terminals

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11
Q

Two types of presynaptic receptor

A
  • Autoreceptor:
    stimulated by transmitter
    released from that nerve
    ending
    -usually inhibitory
  • Heteroreceptor:
    stimulated by other
    transmitters released from
    other nerve endings
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12
Q

Agonist and its types

A

A drug capable of binding and activating a receptor, leading to a
pharmacological response that may mimic that of a neurotransmitter. Can be
classified as full, partial or inverse.
* Full agonist -
* Partial agonist
* Inverse agonist -

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13
Q

Full Agonist

A

Capable of eliciting a maximal response as it displays full efficacy at that receptor.

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14
Q

Partial Agonist

A
  • Binds to and activates a receptor but is only able to elicit
    partial efficacy at that receptor. A maximal effect cannot be produced,
    even when the concentration is increased. When full and partial agonists
    are present the partial agonist may act as a competitive antagonist.
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15
Q

Inverse agonist

A

Produces an effect that is pharmacologically opposite to
an agonist, yet acts at the same receptor. The receptor must elicit intrinsic
or basal activity in the absence of a ligand and the addition of an inverse
agonist will decrease the activity below the basal level.

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16
Q

Antagonist

A

Any substance that does not produce a biological response on
binding to a receptor, but instead blocks or reduces the effect of
an agonist. It may be competitive or non-competitive.
* Competitive antagonist: The drug binds selectively to a
receptor without causing activation but in such a way to
prevent binding of the agonist. The antagonism may be
reversible; the effect can be overcome by increasing the
concentration of the agonist, which will lead to a shift in the
equilibrium.
* Non-competitive antagonist: The drug may block the action of
the receptor by binding to a different site than that activated
by the agonist.

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17
Q

ALLOSTERIC MODULATOR

A

A drug that binds to a receptor at a site distinct from the active
site. A conformational change is induced in the receptor, altering
the affinity of the receptor for the endogenous ligand.
* Positive allosteric modulators - Increase the affinity of the
receptor for the endogenous ligand.
* Negative allosteric modulators - Decrease the affinity of the
receptor for the endogenous ligand.

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18
Q

Termination of NT

A
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19
Q

CATECHOLAMINES

A

Dopamine (DA), norepinephrine (NE), epinephrine (Epi)

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20
Q

NE Implicated in:

A

Sleep, arousal, attention, learning, memory,
depression, anxiety disorders

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21
Q

DA implicated in:

A

Motor activity, cognitive function, emotion, motivation,
neuroendocrine function, Parkinson’s disease,
schizophrenia, drug addiction (DA)

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22
Q

Where are dopaminergic cell bodies mostly located?

A

ventral
tegmental area (VTA) and
substantia nigra

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23
Q

3 dopaminergic systems?

A
  • Mesolimbic system: from the VTA
    to the ventral striatum (nucleus
    accumbens)
  • Mesocortical system: from the
    VTA to frontal and prefrontal cortex
  • Nigrostriatal system: from the
    substantia nigra to the striatum
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24
Q

norepinephrine cell bodies are located where?

A

Norepinephrinergic cell bodies are
mainly located in the locus
coeruleus

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25
Q

Norepineprhinc projections project to where?

A

cortex, thalamus,
amygdala, hippocampus, olfactory
bulb and cerebellum

26
Q

Catecholamine Biosynthesis

A
27
Q

Tyrosine Hydroxylase (TH)

A

Rate-limiting step to control neuronal concentrations of all catecholamines
Activity of TH is dynamically altered to meet demands of release:

28
Q

Pharmacological inhibition of
catecholamine synthesis

A

TH can be inhibited by a-methyl-tyrosine
– Will decrease NE, DA and Epi levels
– Sometimes used in Rx of pheochromocytoma

  • Dopamine BetaHydroxylase can be inhibited by disulfiram
    – Selectively decreases NE (and EPI)
  • Are also experimental PNMT inhibitors to selectively
    decrease EPI
29
Q

Dopamine - receptors

A

All GPCRs
* Five types, divided in two classes:
– D1-like: D1, D5 →Gs
* Mainly postsynaptic; highly abundant in striatum and cortex
* D5 has a much higher affinity for DA than D1 (20 times)
* Implicated in impulse control and mania
– D2-like: D2L, D2S,D3, D4 →Gi/Go
* Both postsynaptic and presynaptic
* D2: key role in schizophrenia and extrapyramidal movement
* D3: implicated in addiction (debated association with G-protein)
* D4: possible target for clozapine?

30
Q

What elevates dopamine levels?

A

NATURAL REWARDS ELEVATE DOPAMINE LEVELS + drugs

31
Q

MECHANISM OF ACTION OF
AMPHETAMINES

A

transported to the presynaptic
neurons by DAT
* Amphetamines interfere with
vesicular monoamine transporter
(VMAT), resulting in increase of non-
vesicular release of dopamine,
norepinephrine and serotonin
* In addition, amphetamines activate
TAAR-1 (Trace amine-associated
receptor-1; endogenous ligand: PEA)

32
Q

Norepinephrine - receptors

A
  • All GPCRs
  • Three major types (α1, α2 and β):
33
Q

Inactivation of Catecholamines

A
  • Reuptake into the presynaptic terminal is major mechanism
  • Dopamine and norepinephrine transporters (DAT, NET).
34
Q

MECHANISMS OF ACTION OF COCAINE

A

Cocaine blocks the dopamine transporter (DAT);
the inhibition of dopamine reuptake leads to increased levels of
dopamine in the nucleus accumbens

35
Q

Which two proteins degrade catecholamines (dopamine)?

A

Catecholamines are primarily degraded by the joint action of monoamine
oxidase (MAO) and catecholamine O-methyl-transferase (COMT)

36
Q

Norepinephrine degradation

A

The degradation of Norepinephrine
is catalyzed by MAO (mainly A)
and COMT

37
Q

degradation table

A
38
Q

MAO and COMT inhibitors

A

MAO A inhibitors: antidepressants
* phenelzine
* tranylcypromine
* isocarboxazid
MAO B inhibitors: selegiline (used for Parkinson’s
Disease)
COMT inhibitor: entacapone (used in Parkinson’s Disease)

39
Q

CHEESE EFFECT

A

Irreversible inhibition
of MAO A causes high
blood pressure and
severe cardiovascular
crises (with risk of
death) if tyramine-
containing food
(typically fermented
food, such as cheese,
wine etc) is eaten

40
Q

Where is serotonin located in CNS?

A

–Serotonergic cell bodies are
mainly located in the raphe
nuclei
–Main Projections: Cortex,
Thalamus, Amygdala,
Hypothalamus, Hippocampus,
Septum, Cerebellum

41
Q

Serotonin –synthesis and degradation

A
42
Q

Serotonin - receptors

A
  • All GPCRs but 5-HT3
  • Seven major classes:
    – 5-HT1: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F →Gi/Go
  • 5-HT1A are mainly autoreceptors
  • Other classes are mainly postsynaptic
    – 5-HT2: 5-HT2A, 5-HT2B, 5-HT2C
  • Typically postsynaptic →Gq
    – 5-HT3: ionotropic (5 subunits, cation-permeable)
  • Antagonists: granisetron, ondansetron and tropisetron (antiemetic)
    – 5-HT4, 5-HT6, 5-HT7: Gs- coupled
43
Q

Actions of SERT and
SERT blockers
SERT == Serotonin Transporters

A
  • SERT mediates reuptake of
    serotonin by co-transport
    with sodium
  • Once internalized, serotonin
    is degraded by MAO-A
  • The action of SERT is similar
    to that of most other
    transporters (such as NET for
    norepinephrine, DAT for
    dopamine and GAT for GABA)
  • SERT blockers, like fluoxetine,
    mediate their action by
    enhancing the synaptic and
    extracellular levels of
    serotonin
  • Chronic blockade of SERT
    leads to antidepressant
    effects
44
Q

what do antidepressants inhibit?

A

Most antidepressants inhibit
serotonin reuptake

45
Q

Acetylcholine –Localization within the brain

A

Interneurons and local
projection neurons:
Striatum (interaction with DA
terminals of neurons projecting
from substantia nigra and VTA) ,
cortex, hippocampus, olfactory
bulb.

Projection neurons:
Ch1 : medial septal nucleus
Ch2: diagonal band of Broca
Ch3: horizontal band of Broca (innervation to the olfactory bulb)
Ch4: magnocellular regions of the preoptic nucleus and nucleus basalis of Meynert;
substantia innominata (projecting to cortex and amygdala).
Ch5 and Ch6 : tegmental areas (projecting mainly to thalamus, hypothalamus and
brainstem)
Ch7: habenula (projecting to interpeduncular nucleus)
Ch8: parabigeminal nucleus (projecting to the superior colliculus).

46
Q

Acetylcholine –synthesis

A
  • Reaction is reversible, but equilibrium
    is strongly shifted to the right.
  • Acetyl CoA – Formed by pyruvate
    dehydrogenase. Most enters the TCA
    Cycle, but some gets into the
    cytoplasm and is then used for ACh
    synthesis.
47
Q

Acetylcholine –nicotinic receptors

A
  • Ionotropic
  • Activated by low concentrations
    and blocked by high
    concentrations of nicotine
  • 5 subunits in 4 major families
    (2α, β, γ, δ)
  • induce EPSP (permeable to
    cations)
  • Different αsubunits condition
    the variable physiological
    significance
48
Q

Acetylcholine –muscarinic receptors

A
  • G-protein-coupled receptors
  • Five genes (M1 to M5)
  • Two major pharmacological classes:
    – M1 (blocked by pirenzepine) →Gq
    – M2 (blocked by gallamine) →Gi / Go
49
Q

GABA –Localization within the CNS

A

GABA is the most ubiqituous inhibitory
neurotransmitter in the brain
In several regions, GABAergic cells occur at high
densities: striatum (95%), globus pallidus,
substantia nigra reticularis, cerebellum,
thalamus, hippocampus and cortex
(interneurons)

50
Q

What breaks down ACh?

A

acetylcholine-esterase

51
Q

GABA Synthesis and Metabolism
(“The GABA Shunt”)

A
52
Q

GABA A receptors

A
  • Ionotropic
  • Ubiqituous in the CNS (both neurons
    and glia)
  • 5 subunits in 4 major families (2α, β,
    γ, δ)
  • induce IPSP (permeable to Cl-)
  • Different subunit composition
    conditions the pharmacological
    response
  • Functional behavior is inhibited by
    most cations (H+, Zn 2+ etc.)
  • Several neurosteroids can affect the
    conductance
53
Q

GABA B receptors

A
  • Metabotropic (GPCR) →Gi/Go;
    Association with Ca2+ and K+
    channels
  • Mainly presynaptic
  • Heterodimers of 2 subunits, GABA-B1
    and GABA-B2
  • Prominent in thalamus, superior
    colliculus, cerebellum and dorsal
    horn of spinal cord
  • Expressed in muscles (hence the
    muscle-relaxing action of baclofen)
54
Q

GABA reuptake

A
  • Reuptake into the nerve terminal or glial cells and also by enzymatic
    catabolism in terminal and/or glia
    – GABA can be repackaged into vesicles and used again and/or
    undergo enzymatic degradation
  • Four plasmalemmal GABA transporters cloned to date:
    – GAT-1 (R,H; GAT1 mice) – Neuronal, and probably glial
    – GAT-2 (R; GAT3 mice) – glial
    – GAT-3 (R,H; GAT4 mice) – neurons and glia
    – BGT-1 (R,H; GAT2 mice) – neurons and glia
  • The inhibitor of GAT, tiagabine, is an anti-epileptic drug
55
Q

– GABA Transaminase (GABA-T)

A
  • Inhibited by vigabatrin (-vinyl-GABA); FDA-approved
    anti-epileptic agent
56
Q

Glutamate –Localization within the CNS

A

Glutamate is the most abundant excitatory
neurotransmitter in the CNS
Other amino acids, like aspartate and N-acetyl-
aspartylglutamate, serve as excitatory
neurotransmitters on Glu receptors.
Particularly prominent in the neocortex
(pyramidal cells), as well as hippocampus,
amygdala and other limbic structures

57
Q

Biosynthesis of Glutamate

A
58
Q

Degradation of Glutamate

A
  • Glu released by neurons is taken
    up by astrocytes
  • The Glu is metabolized to
    glutamine (Gln) by glutamine
    synthetase (GS). Glutamine
    synthetase is only found in glial
    cells.
  • The Gln is then transported out
    of the glial cell and taken up by
    Glu nerve terminals.
  • Phosphate-activated
    glutaminase (PAG), found in
    neurons, then converts the Gln
    back into Glu.
59
Q

Ionotropic glutamate receptors

A
  • 4 subunits
  • Occur as homomeric or heteromeric structures
  • All permeable to cations (induce EPSP)
  • Four classes: AMPA, NMDA, Kainate, Delta
  • NMDA
    – Slow, tightly regulated (Mg2+, Zn2+, polyamine, glycine, D- amino
    acids)
  • AMPA
    – Fast
  • Kainate
    – Relatively fast
60
Q

Metabotropic glutamate receptors

A
  • GPCRs
  • Three classes:
    –Group 1 (mGLUR1, mGLUR5) →Gq
    –Group 2 (mGLUR2, mGLUR3) →Gi/Go
    –Group 3 (mGLUR4, mGLUR6, mGLUR7, mGLUR8) →Gi/Go

Cell and Molecular Neuroscience (15 decks)

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