Lec 3 Neurotransmitter Systems I & II Flashcards
1
Q
What are electrical synapses?
A
- very rare, neurons directly coupled so no chemical process need to transduce electrical impulse from one neuron to next
2
Q
7 steps in chemical synaptic transmission
A
- nerve impuse reaches presynaptic nerve terminal
- activation Ca channel and entry Ca into nerve terminal
- Ca triggers neurotransmitter release/exocytosis
- neurotransmitter activates pre and postsynaptic receptors
- receptor activation regulates ion channels to get postsynaptic currents
- neurotransmitter removed from synapse
- vesicles involved in exocytosis are recaptured by endocytosis
3
Q
What types of neurotransmatters involved in the “classic” synapse? What makes it classic?
A
classic = nerve terminal in close approximation to a dendritic spine where receprtors/signaling proteins located
- glutamate
4
Q
What is role of astrocytes in glutamatergic synapses?
A
- surround synapse
- buffer extracellular levels of glutamate to protect neurons from excessive excitation (excitotoxicity)
5
Q
What are the 4 steps of neurotransmitter vesicle formation and recycling in the nerve terminal? [and what mediates]
A
- neurotransmitter packaged into synaptic vesicle via vesicular transport protein on the vesicle membrane
- vesicles bind active zone on nerve terminal plasma membrane for docking/priming
- Ca entry into nerve terminal triggers fusion that allows neurotransmitter release into synaptic cleft
- vesicle recaptured via clathrin mediated endocytosis
6
Q
Where on the nerve terminal plasma membrane do vesicles containing neurotransmitters bind?
A
the active zone
7
Q
What triggers neurotransmitter-containing vesicle to fuse with the nerve terminal plasma membrane and release neurotransmitter into the synapse?
A
Ca comes into nerve terminal
8
Q
What protein mediates endocytosis that allows for recycling of vesicles after they have released neurotransmitter?
A
clathrin
9
Q
What is role of neurotransmitters in neuronal plasticity?
A
- cause some short-lived adaptations in neuronal functon and ion channel regulation
- also cause phosphorylation cascades that lead to changes in transcription factors and thus stable adaptations
10
Q
What are the 3 amino acid neurotransmitters?
A
- glutamate
- GABA
- Glycine
11
Q
What are the 4 types of monamine neurotransmitters?
A
- catecholamines [dopamine, NE, Epi]
- indoleamines [serotonin, melatonin]
- acetylcholine
- histamine
12
Q
What are the 3 types of catecholamines?
A
- dopamine
- norepinephrine [noradrenaline]
- epinephrine [adrenaline]
13
Q
what are the 2 types of indoleamines?
A
- serotonin
- melatonin [in pineal gland only]
14
Q
What are the 2 types of nucleoside neurotransmitters we talk about?
A
- adenosine
- ATP
15
Q
What are two types of lipid derived neurotransmitters?
A
- Anandamine
- 2AG
16
Q
What type of neurotransmitter is NO?
A
gas
17
Q
What are two main types of neurotransmitter receptors?
A
- ligand-gated channels (ionotropic)
- G-protein coupled receptors [GPCR] (metabotropic)
18
Q
What happens in ligand gated neurotransmission?
A
- neurotransmitter binds to site on a multi-subunit (4-5) ion channel that together form pore
- each subunit is single polypeptide with 4 transmembrane domains
- neurotransmitter binds, opens channel to allow ions to flow in/out
- get rapid post-synaptic current
- can be excitatory or inhibitory
19
Q
What are 4 types of neurotransmitters that can pass Na (and sometimes ca) leading to excitatory post-synaptic current?
A
- glutamate
- acetylcholine
- serotonin
- nucleosides
20
Q
What are 2 types of neurotransmitters that pass Cl leading to inhibitory post-synaptic current?
A
- GABA
- glycine
21
Q
What type of neurotransmission with glutamate (receptor type, excite or inhibit)?
A
- excitatory NA/Ca channels [AMPA, NMDA]
- metabotropic mGluR autoreceptor
22
Q
What type of neurotransmission with GABA (receptor type, excite or inhibit)?
A
- inhibitory ligand-gated Cl channel GABA-A
- metabotropic GABA-B and GABA-C
23
Q
What type of neurotransmission with nucleosides (receptor type, excite or inhibit)?
A
bind ligand gated Na channel (and sometimes Ca) leading to excitatory post-synaptic current
24
Q
What type of neurotransmission with acetylcholine (receptor type, excite or inhibit)?
A
nicotinic = ionotropic excitatory Na channel muscarinic = metabotropic
25
What type of neurotransmission with serotonin (receptor type, excite or inhibit)?
```
5HT3 = ligand gated Na excitatory
5HT = Gi
5HT2 = Gq
5HT4-7 = Gs
```
modulatory NT
26
What type of neurotransmission with glycine (receptor type, excite or inhibit)?
- bind ligand gated Cl channel leading to inhibitory post-synaptic current
- only in spine
27
What is path of GPCR neurotransmission?
- neurotransmitter binds site on a single polypeptide with 7 transmembrane domains
- triggers conformational change in associated G protein
- released G protein subunits directly regulate ion channels + trigger secondary messengers/phosphorylation
- can be excitatory or inhibitory
28
How do neutrophic factors undergo neurotransmission?
- bind plasma membrane receptors
- lead directly or indirectly to activation of protein tyrosine kinases which can directly phosphorylate/regulate ion channels
29
How do steroid hormones undergo neurotransmission?
- diffuse passively into neuron's cytoplasm
| - bind cytoplasmic nuclear hormone receptors which then transport into nucleus and act as transcription factor
30
What is the major excitatory neurotransmitter in the brain and spinal cord?
- glutamate
| - 40-50% of all neurons use glutamate
31
What are two major classes of glutamate receptors? purpose of each?
1. ligand gated Na(Ca) -- mediate rapid neurotransmission
| 2. GPCRs -- exert more modulatory effect, serve as autoreceptor
32
What are the 3 types of ligand gated channels that glutamate activates? Differences in each?
- AMPA = most important for rapid neurotransmission, usually flux only Na
- NMDA = flux Ca/NA , deliver Ca signals into neurons which can trigger many forms of plasticity, require co-activation by glycine
- Kainate
33
What is function of glutamate GPCR?
- Gi-linked mGLUR1-8 are autoreceptors
| - negative feedback loop
34
What are autoreceptors? Function?
- expressed on nerve terminal and respond to the neurotransmitter released by those terminals
- linked to Gi so their activation inhibits the nerve terminal = negative feedback
- expressed on most nerve terminals
35
Where does glutamate come from?
- it is an AA part of krebs cycle, derivative of aspartate via transaminase
- present in every cell in body
- only small fraction of neuronal glutamate used as neurotransmitter in vesicles
36
What is function of astrocytes in glutamate neurotransmission?
- most of glutamate that is released as neurotransmitter is taken up by glutamate transporters on astrocytes
- maintains low level of extracellular glutamte need for neuronal survival
37
What is the glutamate-glutamine shunt around glutamine synapses?
- astrocyte takes up glutamate
- in astrocyte: glutamate degraded into glutamine via glutamine synthetase
- glutamine pumped out of astrocyte by active transport and enters nerve terminal
- in nerve terminal: glutamine converted to glutamate by glutaminase
38
What are two NMDA glutamate receptor antagonists?
- phencyclidine (PCP)
| - alcohol
39
What is the major inhibitory neurotransmitter in brain and spinal cord?
- GABA
| - 40% of all neurons in brain use GABA as transmiter
40
What happens if too little GABA-ergic neurotransmission?
seizures
41
What happens if too much GABA-ergic neurotransmission?
coma
42
What type of receptor is GABA-A? Function?
- ligand gated Cl channel
| - inhibitory postsynaptic currents
43
What type of receptor if GABA-B? Function?
- GPCR
- mediates rapid neurotransmission
- acts as autoreceptor
- modulatory effect
44
Where does GABA come from?
- synthesize from cytoplasmic glutamate via glutamate acid decarboxylase (GAD)
45
What enzyme degrades GABA?
- GABA transaminase
46
How is GABA recycled?
- returned to nerve terminal via plasma membrane GABA transporter
47
Where is GABA synthesized?
nucleus acucumbens
48
What levels of GABA in anxiety?
low levels
49
What levels of GABA in huntington disease?
low levels
50
What is effect of anticonvulsant drugs on GABAergic transmission?
- promote GABA-A transmission
either:
-- increase GABA synthesis in brain
-- OR block reuptake into nerve terminals
51
What is effect of sedative-hypnotic drugs (benzos/barbs/EtOH) on GABAergic transmission?
- promote GABA-A receptor function
| - increase ability of GABA to activate receptor
52
What is a potential effect of drugs that block GABA-A?
induce seizures
53
What are the two major inhibitory neurotransmitters in spinal cord?
GABA and glycine
54
Where does glycine mainly function?
- as inhibitory neurotransmitter in spinal cord
55
What is effect of drugs that block glycine receptors?
- induce seizures (convulsants)
56
What is the name of the major class of glycine receptor? type of receptor?
- ligand gated Cl channel
| - called -- strychnine-sensitive glycine receptor [b/c blocked by drug strychnine]
57
What major drug blocks the glycine ligand gated receptor?
strychnine
58
What is glycine's function in the brain?
- binds with low affinity to NMDA glutamate receptors + enhances ability of glutamate to active these receptors
= co-agonist for NMDA glutamate receptors
59
What is role of monamines generally?
- in most cases modulatory
60
Where does dopamine come from? Where is it synthesized?
- tyrosine hydroxylase: tyrosine --> L-DOPA
- DOPA decarboxylase: L-DOPA --> dopamine [DA]
- synthesized in ventral tegmentum [VTA] and Substantia nigra [SN] (midbrain) and arcuate nucleus
61
Where does norepinephrine come from Where is it synthesized?
- same path as dopamine from tyrosine
- plus dopamine B-hydroxylase: DA --> NE
- synthesized in locus ceruleus (pons)
62
Where does epinephrine come from?
- same path as norepinephrine epinephrine
| - synthesized in adrenergic neurons and in adrenal medula
63
By what two enzymes are catecholamines degraded?
- monoamine oxidases (MAOs)
| - catechol-O-methyltransferase (COMT)
64
What protein mediates catecholamines concentration into synaptic vesicles?
VMAT (vesicular monoamine transporter)
65
What are the 3 major dopaminergic nuclei in the brain?
- in midbrain:
- -- substantia nigra [SN]
- -- ventral tegmental area (VTA)
- in hypothalamus:
- -- arcuate nucleus
66
What are the 3 major domainergic pathways?
- nigrostriatal [NS] substantia nigra --> striatum
- mesoLimbic [ML]: VTA --> forebrain, nucleus accumbens [NAc]
- tuberoinfundibular [TI]: arcuate nucleus --> anterior pituitary
67
What is function of nigroStriatal [NS] dopamine pathway?
- modulates extrapyramidal motor function
68
What is function of mesoLimbic [ML] dopamine pathway?
- emotion, reward, motivation, cognition
69
What is function of arcutate nucleus dopamine neurons?
- inhibit prolactin secretion
70
What type of receptors are dopamine receptors?
- all GPCRs
- D1 and D5 coupled to Gs
- D2, D3, D4 coupled to Gi, autoreceptor
71
What is effect of antipsychotic drugs on dopamine receptors?
- antagonists at D2 receptors
72
What is effect of psycho-stimulant drugs [cocaine, meth] on dopamine transmission?
- promote dopamine function
| - inhibit re-uptake [coke] or stimulate release [meth]
73
What causes parkinsons disease?
- loss of substantia nigra dopamine neurons
74
What are levels of dopamine in parkinsons?
low
75
What are levels of dopamine in huntington disease?
high
76
What are levels of dopamine in depression?
low
77
What are 2 main treatments for parkinsons?
- L-DOPA [precursor to dopamine]
| - D2 dopamine receptor agonists
78
What is function of cocaine on dopamine activity?
- inhibits dopamine reuptake so promotes dopamine activity
79
What is effect of drugs of abuse on mesocorticolimbic dopamine path?
all via indirect effect enhance this pathway to reinforce addiction
80
Where is NE synthesized in the brain? Its function?
- locus ceruleus
81
What is effect of noreadrenerginc innervation?
- promotes vigilance and attention
- major NT of sympathetic NS
- plays role in regulation of stress response
82
What types of receptors are the 3 norepinephrine receptors?
All GPCRs
- a1 receptors: coupled to Gq
- a2: coupled to Gi, act as autoreceptors
- B: coupled to Gs
83
What types of drugs tend to act on NE receptors?
- cardiovascular and upper respiratory (anti-allergy)
84
What are 2 possible actions of antidepressant drugs on NE transmission?
- inhibit NE reuptake
| - inhibit MAO
85
Match type of G protein coupled to each of the 3 NE receptors
a1 -- Gq
a2 --Gi
B -- Gs
86
From what amino acid is serotonin/melatonin derived
Tryptophan
87
What is the other name for 5HT
Serotonin
88
How is serotonin synhtesized?
Raphe nucleus (brainstem)
-- tryptophan + tryptophan hydroxylase --> 5-hydroxytryptophan + aromatic amino acid decarboxylase --> 5HT
89
Where does serotonin --> melatonin conversion occur
Pineal gland only
90
What enzyme can degrade serotonin?
MAOs [monamine oxidases]
91
Where is serotonin synthesized?
- raphe nuclei of midbrain
92
What are functions of serotonin neurotransmission?
- regulate stress responses and emotional behavior
| - regulate eating and weight control and circadian rhythms
93
How many types of serotonin receptors are there? Which are ligand gated?
14. Only one [5HT3] is ligand-gated. All others GPCRs
94
What type of receptor is 5HT1?
- serotonin GPCR coupled to Gi
| - Acts as an autoreceptor
95
What type of receptor is 5HT2?
serotonin GPCR coupled to Gq
96
What type of receptor is 5HT3?
serotonin ligand gated
97
What type of receptors are 5HT4-7?
serotonin GPCRs coupled to Gs
98
What are 2 possible mech of antidepressants on serotonin neurotransmission?
- Most inhibit 5HT reuptake
| - Some are MAO inhibtors
99
What are 2 mechs of action that newer antipsychotic drugs usually have?
- Block D2 dopamine receptors AND
| - block 5HT2A receptors
100
What is mech of newer anti-migraine drugs [triptans] on 5HT neurotransmission?
agonists at 5HT1D receptors
101
What is function of 5HT2C receptors?
| Effect of their agonists/antagonists?
- related to control of appetite
- agonists decrease feeding
- antagonists increase feeding → obestity
102
Where does acetylcholine come from?
brainstem nuclei, basal forebrain
- derived from choline:
acetyltransferase: choline + acetyl CoA → acetylcholine
103
What degrades ACh?
acetylcholesterase
104
How is Ach recycled?
degraded by acetylcholneserase in synapse into choline and acetate
Choline taken up by cholinergic nerve terminals
105
Where are cholinergic neurons located?
A small number of neurons in tightly packed nuclei in:
- Brainstem (dorsolateral tegmentum in pons)
- forebrain (meynerts nucleus and medial septal nuclei)
- small number in the striatum
106
What is function of cholinergic brainstem nuclei?
innervate widely many regions of brain, important for sleep cycle control
107
What is function of cholinergic forebrain nuclei? What do they innervate?
innervate hippocampus, important in learning and memory
108
What is function of striatum cholinergic neurons?
modulate striatal-dependent motor function
109
What are functions of Ach in brain? Outside of brain?
In brain:
- cognition, regulate sleep cycles, modulate striatal motor function
Out of brain:
-major NT of autonomic NS and neuromuscular junction
110
What are the two main types of Ach receptors?
Ligand gated nicotinic receptors and GPCR muscarinic receptors
111
What is mech/function of nicotinic receptors?
ligand gated Ach receptors
| - Na and Ca channels, create excitatory current
112
What is mech/function of muscarinic receptors?
GPCR Ach receptors
- several types M1-M5, coupled to Gi or Gq
- serve as auto-receptors
113
What is the relationship between nicotine and ACh neurotransmission?
- nicotine is partial agonist at nicotinic cholinergic receptors
- activates VTA dopamine neurons to promote reward/addiction
114
What disease can you treat with muscarinic cholinergic antagonists?
parkinson's disease
115
What is mech of action of parkinsons disease drugs on ACh neurotransmission?
muscarinic cholinergic antagonists used to treat parkinson's
| - because cholinergic interneurons regulate striatal function
116
What disease can you treat with acetylcholinesterase inhibitors?
dementia/alzheimers
117
What is mech of action of dementia drugs on ACh neurotransmission?
- act as acetylcholinesterase inhibitors
118
What is histamine derived from?
- histidine + histidine decarboxylase --> histamine
119
Where is histamine synthesized?
- hypothalamic tuberomammillary nucleus
120
What is function of histamine in brain?
- promote sedation
121
What type of receptors are the 3 histamine receptors? What is the major important one in brain?
- all GPCRs
| - major receptor in brain is H1
122
What is function of H1 receptor antagonists? location?
- classic "antihistamines"
- used as anti-allergy drugs
- also induce sedation as side effect
- in brain
123
Where is of H2 receptors? location?
- regulate acid secretion [inhibits acid]
| - c in stomach
124
What is function of H3 receptors? Location?
autoreceptor in brain
125
What are 4 ways that peptide neurotransmitters different from small molec neurotransmitters?
1. peptides must be synthesized in cell bodies [vs small molec synthesized locally within nerve terminals]
2. peptides packed to large dense core vesicles in cell bodies and transported to nerve terminals [vs small molec packaged to small clear synaptic vesicles]
3. peptides once released are enzymatically degraded which is irreversible [vs small molec reuptake / recycled back to presynaptic nerve terminal]
4. All peptides act solely on GPCRS [vs many small molec act on ligand gated receptors as well]
126
What type of receptors do peptide transmitters act on?
solely GPCRs (no ligand gated)
127
What is function of hypothalamic releasing and inhibitory factors? Examples?
- utilized by hypothalamic and extra-hypothalamic neurons as neurotransmitters
- regulate pituitary hormone release
- ex: CRF, TRF, GnRF, GHRF, somatostatin
128
What are some [5] examples of feeding and gut-brain peptides?
- NPY (neuropeptide Y)
- a-MSH
- cholecystokinin [CCK]
- glucagon-related peptide [GRP]
- VIP (vasoactive intestinal polypeptide)
129
What is function of tachykinins? example?
- ex: substance P
| - regulate nociception (ability to sense pain)
130
How are peptide neurotransmitters synthesized?
- perpropeptide gene --> mRNA --> protein on RER
- prepropeptide processed to propeptide --> multiple mature mature peptide
- peptides packaged to dense core vesicles for transport
131
What 3 peptides come from POMC propeptide?
- ACTH
- B-endorphin
- a-MSH [a-melanocyte stimulating hormone]
132
What is the basis of neurons using "co-transmitters"?
- most peptidergic neurons also use a small molec neurotransmitter (glutamate, MAO, etc)
133
What is another name for orexin?
hypcretin
134
Where is orexin synthesized?
lateral hypothalamus [but have widespread projections throughout brain]
135
What are the two types of orexin receptors?
- both GPCRS
| - OX1, OX2
136
What is function of orexin?
- promotes alertness/wakefulness
| - also modulate mood, reward, alertness, motivation [via brainstem ACh nuclei]
137
To what 2 places do orexinergic neurons project strongly?
- tuberomammillary nucleus [histamine synthesis site]
| - brainstem nuclei [ACh synthesis site]
138
What is cause of human narcolepsy?
- death [autoimmune-mediated] of orexinergic neurons
| - characterized by suddenly falling into REM sleep during period of wakefullness
139
What are the 3 main types of opioid peptides?
- enkephalins
- endorphins
- dynorphin
140
What are enkephalins derived from? Where synthesized?
- from preproenkephalin
| - synthesized throughout brain and spinal cord
141
What are endorphins derived from? Where synthesized?
- from prePOMC
| - synthesized primarily in hypothalamus
142
What are dynorphins derived from? Where synthesized?
- from preprodynorphin
| - synthesized throughout brain and spinal cord
143
Where are each of the 3 types of opioids synthesized?
- enkephalins and dynorphins throughout brain and spinal cord
- endorphins primarily in hypothalamus
144
What type of receptors to each of the 3 types of opioids act on?
- enkephalins and endorphins act on μ and δ opioid receptors
| - dynorphins act on κ opioid receptors
145
What is function of enkephalins/endorphins?
- promote reward, positive mood, analgesia, sedation
146
What is function of dynorphins?
- promote analgesia and sedation
| - generally induce negative mood state
147
What is primary action of all illegal and prescription opiate drugs?
- primarily μ opioid receptor agonists
148
What is function of nucleoside neurotransmitters?
- modulatory function
149
What are steps of ATP as neurotransmitter?
- ATP packaged in synaptic vesicles and released
- once released can directly activate nucleoside receptors or be converted to adenosine in synaptic space (adenosine can also be released directly from postsynaptic)
150
What types of receptors are nucleoside receptors?
- ~20 types, including ligand and GPCR
151
What is funtion of adenosine neurotransmission?
- regulates alertness and sleep
- adenosine accumulates during wakefulness to promote sleep
- sleep (even brief period) reduces adenosine levels = associated with fatigue
152
What is function of adenosine receptor antagonist? main example?
- promote wakefullness
| - CAFFEINE!!!!!!
153
What are two well-known lipid-derived neurotransmitters? What are they derived from?
- anandamide [AEA]
- 2AG [2-arachidonoylglycerol]
arachidonic acid --> AEA + 2AG
154
What are endocannabinoids? Why name?
- endocannabinoids = lipid derived neurotransmitters anandamine and 2AG
- natural neurotransmitters ligands for GPCRs that are also targeted by cannibus
155
Mech of endocannabinoid action?
- synthesized postsynaptically in response to Ca influx
- released into synapse and act on cannabinoid CB1 receptors on nerve terminal
- decrease NT release
- not stored in vesicles
- "retrograde" synaptic transmission
156
What are the two types of cannabinoid receptors? Which is most important in brain?
- CB1 and CB2
- both GPCRs
- CB1 more improtatn in brain by far
157
What is mech of marijuana action/
- activate CB1 receptors of lipid neurotransmission
158
What is function of endocannabinoids?
- effect brain function, regulate perception, appetite, nociception, reward, and levels of consciousness
159
What is prototypical gas neurotransmitter?
NO [nitric oxide]
160
How is NO synthesized? Where?
- NO synthase: arginine --> NO
| - synthesized postsynaptically in response to Ca influx into neuron
161
What it the path of NO action?
- NO synthesized post-synaptically in response to CA influx into neuron
- passively diffuses into nearby nerve terminals
- activates guanylyl cyclase --> increase cGMP --> modulate release of NTs
162
What is function of NO as neurotransmitter?
- modulatory function in brain
163
What are two examples of retrograde synaptic transmission?
- NO
| - lipid derived neurotransmitters [endocannabinoids]
164
What type of receptors are ionotropic receptors?
ligand gated [rapid transmission]
165
What type of receptors are metabotropic?
GPCRs [slower postsynaptic response]
166
How are lipid NTs degraded?
by fatty acid amide hydrolysis in glial cells
167
What is role of lipid neurotransmission in glutamate synapses?
- glutamate synapses have presynaptic CB receptors to protect against excitotoxicity
168
What is function of melatonin?
regulate sleep-wake cycles
