Receptors, Neurotransmitters, and Signal Transduction Flashcards
1
Q
What is the action of an inotropic receptor?
A
Excitability
NT binding –> Na+ influx (excitation) or Cl- influx (inhibition)
2
Q
What is the composition of an inotropic receptor?
A
Composed of multiple transmembrane receptors that form an ion channel
3
Q
What are some examples of inotropic receptors?
A
NMDA, nicotinic ACh, 5HT-3, GABA-A
4
Q
What is the composition of a metabotropic receptor?
A
- GPCRs
- Each receptor generally has 7 transmembrane regions
5
Q
What is the action of a metabotropic receptor?
A
Genetic transcription via a second messenger system (cAMP or IP3)
The second messengers can affect both gene transcription and ion channel permeability
6
Q
What are some examples of metabotropic receptors?
A
ACh, catecholamines (NE, epi, DA), peptides, and serotonin
7
Q
What is the action of receptor tyrosine kinases?
A
Synaptic plasticity via gene transcription
Activation of these receptors by growth factors and neurotrophic factors can influence axon generation, migration, apoptosis, and plasticity
8
Q
What is the action of nuclear receptors?
A
Lipophilic ligands (hormones) pass through the membrane and bind cytoplasmic receptors, these then enter the nucleus and influence gene transcription
9
Q
What is the action of somatodendritic autoreceptors?
A
Regulation of the presynaptic neuron’s firing rate; generally these are inhibitory
K+ channels open –> decreased cAMP
10
Q
What is the action of nerve terminal autoreceptors?
A
To decrease the amount of NT released from the presynaptaic neuron by closing Ca2+ channels
11
Q
What are heteroreceptors?
A
Pre-synaptic GPCRs with non-specific ligands that are always inhibitory
12
Q
Explain the mechanism of receptor desensitization.
A
Over phosphorylation of GPRC –> binding of arrestin protein –> blockage of G-protein cascade –> receptor reset
13
Q
Explain the mechanism of receptor down-regulation.
A
Prolonged desensitization –> internalization and degradation of the GPCR
14
Q
Explain the mechanism of receptor up-regulation.
A
Chronic antagonism of the GPCR –> increased receptors on the membrane –> increased sensitivity to the NT
15
Q
Explain the mechanism of tardive dyskinesia.
A
Chronic D2 blockade –> increased D2 receptor expression –> increased sensitivity to DA
Therefore, treatment with medications that increase DA will make TD worse.
TD movements end up looking similar to that of patients with excess DA
16
Q
Describe the pathophysiologic differences in TD and EPS
A
EPS is caused by too little DA (hypokinetic), and adding DA improves the condition (anticholinergics decrease ACh but increase DA)
TD is caused by hypersensitivity to DA due to the increased number of receptors
17
Q
What are the 5 criteria for a NT?
A
- NTs are synthesized and released from neurons
- NTs are released from nerve terminals in chemically or pharmacologically identifiable form
- NTs interact with post-synaptic receptors and have the same effect on both the pre- and post-synaptic neurons
- Interaction with postsynaptic receptor displays a specific pharmacology
- Actions are terminated by active processes
18
Q
Describe the action of partial agonist?
A
A ligand that has a weaker effect on ion channels or second messenger systems.
Alone, it acts as a weak agonist. In the presence of a full agonist, it will compete with/act as an antagonist of the full agonist.
19
Q
Describe the action of an antagonist.
A
A ligand with no intrinsic activity of its own. When bound to a receptor alone, the receptor stays in its resting state.
In the presence of an agonist, an antagonist works to block the agonist and to return the receptor to its resting state.
Overall, an antagonist will return a receptor to its basal activity.
20
Q
Describe the action of an inverse agonist.
A
A ligand that will depress receptor activity.
**An antagonist in the presence of an inverse agonist would return the receptor to its basal activity.
21
Q
What are the projections of the serotonergic system?
A
From the Raphe nucleus to:
- Frontal cortex –> mood
- Basal ganglia (5HT-2A/C) –> repetitive movement and OCD
- Limbic area –> anxiety and panic
- Hypothalamus (5HT-3) –> regulation of appetite and eating behavior
22
Q
Describe the production of serotonin.
A
L-tryptophan in presynaptic neuron –> 5-hydroxytryptophan (5HTP) via tryptophan hydroxylase
5HTP is converted to serotonin (5HT) and packaged into vesicles by VMAT
23
Q
Describe the destruction of serotonin.
A
Serotonin in the synaptic cleft undergoes reuptake via transporters (5HTT). From there, serotonin is either:
- repackaged for re-release
- broken down to 5-HIAA via monoamine oxidase (MAO) in the mitochondria
24
Q
What heteroreceptors modulate serotonin?
A
- Pre-synaptic alpha1 receptors bind NE –> increased 5HT release
- Pre-synaptic alpha2 receptors bind NE –> decreased 5HT release
25
Describe the action of serotonin transporters (5HTT).
5HTTs co-transport 5HT and Na+ into the cell while shuttling K+ outside the cell.
26
5HT-1A
Metabotropic GPCR
- Pre-synaptic receptors are somatodendritic autoreceptors (open K+ channels --> increased firing rate)
- Post-synaptic receptors are associated with expression of trophic factors (promote axon branching) --> SSRIs promote hippocampal neurogenesis
- Antagonists --> synaptic losses and play a role in mood disorders
27
5HT-1B
Nerve terminal auto-receptor --> decreased NT release
28
5HT-1D
Nerve terminal auto-receptor --> decreased NT release
29
5HT-2A
Post-synaptic receptor
- Basal ganglia projections control movement and compulsions
- Mesocortical projections --> decreased DA --> apathy and low libido
- Stimulation of these receptors --> inhibition of orgasm/ejaculation
- Limbic projections --> decreased panic/anxiety
30
5HT-2C
- Limbic projections --> decreased panic/anxiety
- Causes weight gain
31
How do SSRIs affect 5HT-2 receptors?
Downregulation of 5HT-2 --> improved 5HT:receptor ratio (serotonin deficit hypothesis)
32
5HT-3
Inotropic receptors
- Responsible for the GI effects of SSRIs
- Hypothalamic projections regulate appetite and satiety
33
What are the projections of the dopaminergic system?
1. Mesolimbic
2. Mesocortical
3. Nigrostriatal
4. Tuberoinfundibular
34
Describe the mesolimbic dopaminergic pathway.
VTA --> hypothalamus --> limbic system, frontal lobe, and nucleus accumbens
- Associated with reward behaviors and addiction
- Excess DA in this system is associated with (+) symptoms of schizophrenia and aggression
35
Describe the mesocortical dopaminergic pathway.
VTA --> cortex and limbic system
- Associated with cognition and motivation
- Deficiency of DA in this system is associated with (-) symptoms and cognitive issues in schizophrenia
36
Explain the pathophysiology of schizophrenia.
Overactive mesolimbic pathway and underactive mesocortical pathway
37
Describe the nigrostriatal dopaminergic pathway.
Reticular formation + substantia nigra --> caudate nucleus + putamen
- Deficiency of DA --> Parkinsonian symptoms, akathisia, dystonia
- Excess DA --> chorea, diskinesia, tics
38
Describe the tuberoinfundibular dopaminergic pathway.
Hypothalamus --> anterior pituitary --> inhibits prolactin release
- DA blockade --> increased prolactin --> galactorrhea, amenorrhea, sexual dysfunction
39
Explain how DA is produced.
L-tyrosine in pre-synaptic neuron --> L-DOPA via tyrosine hydroxylase --> DA by dexarboxylase --> packaged into vesicles by VMAT
40
Explain how DA is destroyed.
Reuptake into the pre-synaptic neuron via DAT, then it is either
- Repackaged into vesicles and recycled
- Broken down into dihydroxyphenylalanine or HVA by MAO
41
How does the DA transporter work?
Na+/K+ pump
42
How do amphetamines affect the DA transporter?
They reverse the direction of the transporter to *release* DA
43
How does cocaine affect DA levels?
It blocks the reuptake of DA
44
Discuss the D1 receptor.
GPCR that stimulates adenylyl cyclase
- Highest density in the frontal cortex (mesocortical pathway) and is involved in cognitive functioning
45
Discuss the D2 receptor.
GPCR that inhibits adenylyl cyclase
- On pre-synaptic neurons, these autoreceptors are both somatodendritic and nerve terminal
- Post-synaptically, they have the highest density in the striatum and nucleus accumbens (nigrostriatal, mesolimbic)
46
Discuss the D3 receptor.
GPCR that inhibits adenylyl cyclase
- Highest density in the amygdala and hippocampus (mesolimbic)
- Important target for antipsychotics
- May interact with BDNF
47
Discuss the D4 receptor.
GPCR that inhibits adenylyl cyclase
- Highest density in the midbrain, amygdala, and frontal cortex (mesolimbic) and *minimal* presence in the striatum
- Clozaril has a high affinity for this receptor and has minimal EPS d/t limited striatal DA blockade
- Associated w/ thrill-seeking behavior and ADHD
48
Discuss the D5 receptor.
GPCR that stimulates adenylyl cyclase
- Highest density in limbic areas (amygdala and hippocampus) and is associated w/ memory consolidation
49
What class of NT is norepinephrine?
Monoamine, catecholamine
50
What are the projections of the noradrenergic system?
From the locus coeruleus to:
1. Frontal cortex (mood)
2. Prefrontal cortex (attention)
3. Limbic system (emotions, energy, fatigue, PMR/A)
4. Cerebellum (motor movement and tremor)
5. PNS (cardiovascular and sympathetic systems)
51
Explain the production of norepinephrine.
DA --> NE via DA beta-hydroxylase (DBH). NE is then packaged into vesicles and released.
- DA neurons lack DBH and cannot produce NE
52
Explain the destruction of norepinephrine.
NE --> normetanephrine via COMT
Normetanephrine --> MHPG via monoamine oxidase (MAO)
53
How does clonidine affect the noradrenergic system?
Antagonizes pre-synaptic alpha-2 receptors --> decreased firing rate and release of NE
54
How does prazosin affect the noradrenergic system?
Prazosin is an alpha-1 inverse agonist
55
How do SSRIs affect the noradrenergic system?
SSRIs down-regulate NE transporters --> less NE reuptake --> more NE in the synaptic cleft
56
Describe alpha-1 receptors.
Post-synaptic GPCRs that activate phospholipase C
- alpha-1 heteroreceptors on presynaptic 5HT neurons increase the amount of 5HT in the brainstem
57
Describe alpha-2 receptors.
Pre-synaptic GPCRs that inhibit adenylyl cyclase
- Can also act as heteroreceptors for 5HT --> inhibited release
- Can be found post-synaptic in the frontal cortex (controls cognition and focus)
58
Describe beta-1 receptors.
GPCRs that activate adenylyl cyclase
- Responsible for modulating mood in the frontal cortex; the most effective antidepressants down-regulate these receptors
- beta-1 antagonists may help treat PTSD by regulating emotional memories
59
Describe beta-3 receptors.
GPCRs
- Not located in the CNS, but instead in brown fat; activation --> lipolysis and thermogenesis
- beta-3 agonists may be developed in the future as a treatment for obesity
60
What are the physiologic effects of alpha-1 receptors?
- Blood vessels: vasoconstriction
- Heart: increased contractility
- Kidneys: vasoconstriction
61
What are the physiologic effects of alpha-2 receptors?
- Blood vessels: vasoconstriction
- Thrombocytes: aggregation
- Kidneys: vasoconstriction
- Adipocytes: inhibition of lipolysis
62
What are the physiologic effects of beta-1 receptors?
- Heart: tachycardia, increased contractility
- Kidneys: renin release, inhibition of tubular sodium reabsorption
- Adipocytes: lipolysis
63
What are the physiologic effects of beta-2 receptors?
- Blood vessels: dilatation
- Bronchi: relaxation
- Kidneys: renin release, inhibition of tubular sodium reabsorption
- Adipocytes: lipolysis
64
What are the projections of the cholinergic system?
From the hippocampus to:
- Basal nucleus of Meynart
- Medial septal nuclei
65
What is the primary function of the cholinergic system?
Memory, cognition, learning, and attention.
66
What NT system is implicated in Alzheimer's disease?
Cholinergic
67
Explain the production of ACh.
Choline crosses the BBB and is actively transported into the presynaptic terminals
Choline accepts an acetyl group from acetyl coenzyme A and is converted into ACh --> packaged into vesicles for release
68
Explain the destruction of ACh.
Acetylcholinesterase breaks down ACh in the synaptic cleft
Free ACh is transported back into the presynaptic neuron for recycling or destruction
69
Where are ACh autoreceptors located?
Presynaptic neurons
70
What is the effect of botulism on the cholinergic system?
Prevents presynaptic Ach vesicle release
71
What role does the cholinergic system play in Lambert-Eaton syndrome?
Antibodies against presynaptic Ca2+ channels --> decreased ACh release
72
What role does the cholinergic system play in myasthenia gravis?
IgG antibodies against the post-synaptic nicotinic recepotrs --> paralysis
73
Describe the M1 receptor.
Most abundant receptor in the cortex and hippocampus
- Located post-synaptically on pyramidal neurons
- Plays a role in enhancing glutamate transmission via NMDA receptors
- Related to learning and memory and may be associated w/ dementia
74
Describe the M2 receptor.
Primary autoreceptor in cortical structures
- Located peripherally and has a parasympathetic effect on the heart
- Antagonized by atropine
75
Describe the M3 receptor.
Located peripherally on smooth muscle cells; has a parasympathetic effect --> vasodilation, pupillary dilation, gland secretion, and GI activation
- Associated w/ insulin resistance and weight gain in atypical antipsychotics
76
Describe the M4 receptor.
Most abundant in the striatum
- This receptor is affected in Alzheimer's disease
- M1/M4 agonists have shown improvement in cognitive and behavioral symptoms of schizophrenia and Alzheimer's
77
Describe neuronal nicotinic ACh receptors.
Presynaptic inotropic receptors
- Modulate ACh, 5HT, Glu, DA, and NE neurotransmission
78
How are neuronal nicotinic ACh receptors implicated in schizophrenia?
Schizophrenics have abnormal nACh receptors --> cognitive deficits
Schizophrenics have abnormal expression of the alpha-7 nACh receptor, which is involved in filtering auditory information
79
What is a hypothesis as to why patients w/ schizophrenia have a higher rate of cigarette use?
This may be an unconscious attempt to correct nicotinic ACh abnormalities
80
What is the effect of aspartate as a NT?
Excitatory amino acid
81
What are the primary effects of the glutamatergic system?
Glutamate is an excitatory amino acid --> action potentials are more likely to occur
- Associated with neuromodulation (pruning), plasticity, and memory
- It is a potent neuronal excitotoxin, with Ca2+ influx into cells --> cell death
82
Explain the production of glutatmate.
Glutamate does not pass the BBB. It is produced locally by enzymes in neurons and glial cells
- Glucose is transaminated b GABA-T in neurons
- Released by Ca2+ dependent exocytosis
83
Explain the destruction of glutamate.
Reuptake into pre-synaptic neurons and astrocytes.
84
How is glutamate implicated in mood disorders?
Excess Glu signalling --> cytotoxicity and astrocyte loss --> mood disorders
85
Describe the AMPA receptor.
Excitatory inotropic receptor activated by Glu
- AMPA's membrane depolarization can dislodge the Mg that blocks NMDA --> assisted activation of NMDA
86
Describe the kainate receptor.
Shares similar properties to AMPA
87
Describe the NMDA receptor.
Excitatory inotropic receptor that is both ligand gated (binds Glu) and voltage-gated (requires AMPA activation to depolarize the cell)
Requirements for NMDA activation:
- AMPA activation must displaces Mg2+ from NMDA
- 2 molecules of glycine (co-agnoists) must bind NMDA NR1 subunit
- 2 molecules of Glu must bind NMDA NR2 subunit
Activation --> Ca2+ influx and a cascade that involves protein kinases and gene transcription
88
Name some NMDA antagonists.
- PCP
- Ketamine
- Amantadine
- Memantine
89
How is NMDA implicated in Huntington's and Alzheimer's?
These diseases are associated w/ excitotoxicity
- Memantine may help slow the progression of these diseases
90
How does clozapine affect NMDA receptors?
Enhances NMDA receptor activity
91
Explain the relationship between NMDA modulators and schizophrenia.
Glycine agonists (D-serine) and glycine reuptake inhibitors (sarcosine) improve cognition and reduce negative symptoms in schizophrenics receiving antipsychotics.
92
Describe metabotropic glutamate receptors (mGluR).
@@@ (PRITE Ninja page 30)
93
Explain synaptic plasticity.
The ability for synapses to strengthen or weaken over time
This is more related to signal strength than to chronic agonism or antagonism
94
Explain long-term potentiation in synaptic plasticity.
Synapses w/ strong depolarization and large Ca2+ influx end up making more receptors and strengthening signal transmission
- Leads to increase in AMPA receptors
- "Survival of the fittest"
95
Explain long-term depression in synaptic plasticity.
Long-term potentiation must be balanced--when some synapses strengthen, others weaken
Synapses w/ weak depolarization make less receptors and overall the synapse weakens
- Leads to decreased AMPA receptors
- "Culling the herd"
96
How are long-term potentiation and depression implicated in learning and memory?
Induction of these processes occurs in the hippocampus and is dependent on NMDA receptor activation
97
What pathologies are caused by excitotoxicity?
- Spinal cord injury
- Stroke
- TBI
- Neurodegenerative diseases
98
Explain the process of excitotoxicity.
Excessive Glu signalling --> excess intracellular Ca2+. This disrupts the cytoskeleton and mitochondria --> cell death.
99
Explain the two pathways of glycine production.
1. Serine is reversibly transformed into glycine via serine-trans-hydroxymethylase (this is folate-dependent)
2. Glyoxylate is converted to glycine via D-glycerate dehydrogenase
100
Describe the function of glycine as a NT.
Found in high concentrations in the brain stem and spinal cord.
- Augments NMDA receptor opening
101
What is the primary function of the GABAergic system?
GABA is the primary inhibitory neurotransmitter
GABA opens Cl- channels and hyperpolarizes/inhibits the neuron
102
Explain the production of GABA.
Glu --> GABA via glutamic acid decarboxylase
103
Explain the destruction of GABA.
GABA reuptake -->
1. Repackaging and re-release OR
2. Conversion into alpha-ketoglutarate and eventually Glu via GABA transaminase (GABA-T)
104
What is the GABA shunt?
The conversion of GABA into alpha-ketoglutarate and eventually Glu via GABA transaminase (GABA-T)
Glu the re-enters the neuron and can be converted back into GABA again
105
What are some examples of positive allosteric modulators of GABA?
- Benzodiazepines
- Barbiturates
- Alcohol
106
What drug is the primary GABA antagonist?
Flumazenil
- Used in benzodiazepine and barbiturate overdoses
107
Describe the GABA-A receptor.
Inotropic transmembrane Cl- channel that opens when activated --> hyperpolarization
- Made up of 5 polypeptide subunits (alpha, beta, delta, epsilon, gamma)
108
How do benzodiazepines affect the GABA system?
- Binds to the alpha-1 subunit of GABA-A --> sedation
- Binds to the alpha-2 subunit of GABA-A --> anxiolytic effects
109
Describe the GABA-B receptor.
GPCR that inhibits adenylyl cyclase --> open K+ channels and closed Ca2+ channels
- Not closely linked to anxiety disorders or anxiolytics
110
What are the 2 possible actions of antiepileptics?
1. Enhancement of inhibition
2. Reduction of excitation
111
What antiepileptics enhance neuronal inhibition?
1. Phenobarbital (activates GABA-A)
2. Benzodiazepines (activates GABA-A)
3. Vigbatrin (inhibits GABA degradation by blocking GABA-T)
4. Tiagabine (inhibits GABA reuptake)
5. Gabapentin
112
What antiepileptics reduce excitation?
1. Phenytoin (inhibits Na+ channel)
2. Carbamazepine (inhibits Na+ channel)
3. Lamotrigine (inhibits Na+ channel)
4. Felbamate
5. Topiramate (inhibits NMDA and non-NMDA receptors)
6. Ethosuximide (inhibits Ca2+ channel)
7. Ketamine (inhibits NMDA receptors)
8. Mg2+ (inhibits NMDA receptors)
113
What is the function of nuclear hormones?
Lipophilic hormones permeate neuronal cell membrane and enter the nucleus to act as a transcription factors that either inhibit or activate gene transcription.
