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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
Norepineprhinc projections project to where?
cortex, thalamus, amygdala, hippocampus, olfactory bulb and cerebellum
26
Catecholamine Biosynthesis
27
Tyrosine Hydroxylase (TH)
Rate-limiting step to control neuronal concentrations of all catecholamines Activity of TH is dynamically altered to meet demands of release:
28
Pharmacological inhibition of catecholamine synthesis
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
Dopamine - receptors
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
What elevates dopamine levels?
NATURAL REWARDS ELEVATE DOPAMINE LEVELS + drugs
31
MECHANISM OF ACTION OF AMPHETAMINES
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
Norepinephrine - receptors
* All GPCRs * Three major types (α1, α2 and β):
33
Inactivation of Catecholamines
* Reuptake into the presynaptic terminal is major mechanism * Dopamine and norepinephrine transporters (DAT, NET).
34
MECHANISMS OF ACTION OF COCAINE
Cocaine blocks the dopamine transporter (DAT); the inhibition of dopamine reuptake leads to increased levels of dopamine in the nucleus accumbens
35
Which two proteins degrade catecholamines (dopamine)?
Catecholamines are primarily degraded by the joint action of monoamine oxidase (MAO) and catecholamine O-methyl-transferase (COMT)
36
Norepinephrine degradation
The degradation of Norepinephrine is catalyzed by MAO (mainly A) and COMT
37
degradation table
38
MAO and COMT inhibitors
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
CHEESE EFFECT
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
Where is serotonin located in CNS?
–Serotonergic cell bodies are mainly located in the raphe nuclei –Main Projections: Cortex, Thalamus, Amygdala, Hypothalamus, Hippocampus, Septum, Cerebellum
41
Serotonin –synthesis and degradation
42
Serotonin - receptors
* 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
Actions of SERT and SERT blockers SERT == Serotonin Transporters
* 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
what do antidepressants inhibit?
Most antidepressants inhibit serotonin reuptake
45
Acetylcholine –Localization within the brain
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
Acetylcholine –synthesis
* 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
Acetylcholine –nicotinic receptors
* 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
Acetylcholine –muscarinic receptors
* 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
GABA –Localization within the CNS
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
What breaks down ACh?
acetylcholine-esterase
51
GABA Synthesis and Metabolism (“The GABA Shunt”)
52
GABA A receptors
* 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
GABA B receptors
* 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
GABA reuptake
* 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
– GABA Transaminase (GABA-T)
* Inhibited by vigabatrin (-vinyl-GABA); FDA-approved anti-epileptic agent
56
Glutamate –Localization within the CNS
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
Biosynthesis of Glutamate
58
Degradation of Glutamate
* 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
Ionotropic glutamate receptors
* 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
Metabotropic glutamate receptors
* 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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