Monoamines & Atypicals Flashcards
(349 cards)
1
Q
What are most classical monoamine neurotransmitters derived from
A
The amino acid tyrosine.
2
Q
What is Serotonin (5-HT) derived from
A
The amino acid tryptophan.
3
Q
Where is tryptophan obtained from
A
The diet.
4
Q
What enzyme is involved in both catecholamine and serotonin biosynthesis pathways
A
AADC (aromatic l-amino acid decarboxylase or DOPA decarboxylase).
5
Q
How are monoamines eliminated
A
By reuptake and degradation.
6
Q
What are the specific high-affinity reuptake transporters for dopamine noradrenaline and serotonin
A
DAT NET and SERT.
7
Q
What are general low-affinity reuptake molecules for monoamines
A
OCT3 and OCT2.
8
Q
What is another low-affinity transporter for DA and 5-HT
A
Plasma membrane monoamine transporter.
9
Q
What transporter is involved in recycling and sequestering monoamines into vesicles
A
VMAT (vesicular monoamine transporter).
10
Q
What enzyme is associated with the mitochondrial outer membrane and degrades monoamines
A
Monoamine oxidase (MAO).
11
Q
What are the two forms of MAO
A
MAO-A and MAO-B.
12
Q
What monoamines are selectively degraded by MAO-A
A
Serotonin Noradrenaline Adrenaline Octopamine.
13
Q
What monoamines are selectively degraded by MAO-B
A
Phenylethylamine Benzylamine.
14
Q
What monoamines can both MAO-A and MAO-B degrade
A
Dopamine Tyramine Tryptamine.
15
Q
Where does MAO act
A
Intracellularly.
16
Q
What enzyme targets catecholamines
A
Catechol-O-methyltransferase (COMT).
17
Q
Where does COMT act
A
Intracellularly in membrane-bound form and extracellularly in the synapse.
18
Q
What is the rate-limiting enzyme in dopamine biosynthesis
A
Tyrosine hydroxylase.
19
Q
What does tyrosine hydroxylase do
A
Adds a hydroxyl group to tyrosine turning it into L-DOPA.
20
Q
What cofactors are required by tyrosine hydroxylase
A
Tetrahydrobiopterin O2 and Fe2+.
21
Q
What does dopa decarboxylase (AADC) do in DA synthesis
A
Removes a carboxyl group from L-DOPA turning it into dopamine.
22
Q
What cofactor is required by AADC in DA synthesis
A
Pyridoxal phosphate.
23
Q
Where is dopamine produced in dopaminergic neurons
A
In the presynaptic terminal.
24
Q
How is dopamine stored in synaptic vesicles
A
Sequestered into the acidic lumen via VMAT2.
25
What is the function of the acidic environment in synaptic vesicles for dopamine
It **stabilizes** it and **prevents oxidation**.
26
How many types of dopamine receptors are there
**5** types (D1 to D5).
27
What are the two general categories of dopamine receptors
**D1-like** and **D2-like**.
28
What does D1-like receptors typically do to AC activity
**Stimulate** it.
29
What G protein are D1-like receptors associated with
**Gαs/olf**.
30
What is the effect of Gαs/olf coupling for D1-like receptors
Leads to **higher levels of cAMP** and stimulating **PKA activity**.
31
When are D1-like receptors thought to be preferentially activated
By **high concentrations** of dopamine **phasic release**.
32
What does D2-like receptors typically do to AC activity
**Inhibit** it.
33
What G protein are D2-like receptors associated with
**Gαi/o**.
34
What is the effect of Gαi/o coupling for D2-like receptors
Inhibiting adenylyl cyclase and **reducing intracellular cAMP** which blocks **PKA activity**.
35
What are D2-like receptors thought to be responsible for detecting
**Tonic low levels** of dopamine.
36
Does dopamine always have the same effect
No it can have an **excitatory or inhibitory effect** depending on which receptor it binds to.
37
What are some targets of PKA
**CREB** **glutamate receptors** **GABA receptors** and **ion channels**.
38
What other G protein can dopamine receptors couple to
**Gαq**.
39
What does Gαq coupling lead to
Production of **IP3** and **DAG** increasing **intracellular calcium** and activating **PKC**.
40
What enzymes are activated by increased calcium downstream of DA receptors
**PP2B** and **CaMKII**.
41
What do βγ-subunits regulate
**Ion-channel activity**.
42
What other pathways can dopamine receptor signalling be mediated by
**Gq** and **β-arrestin pathways**.
43
What other receptors can dopamine activate
**TAARs** and **α2 adrenoceptors**.
44
Where are dopamine receptors expressed
Widely in the **CNS** and **peripherally**.
45
Where are D1-like receptors mostly found in the CNS
**Caudate–putamen** (striatum) **nucleus accumbens** **substantia nigra pars reticulata** **olfactory bulb** **amygdala** and **frontal cortex**.
46
Where are D2-like receptors mainly expressed
**Striatum** **globus pallidus** **nucleus accumbens** **ventral tegmental area** **hypothalamus** **amygdala** **cortical areas** **hippocampus** and **pituitary**.
47
Where are DA receptors particularly concentrated
In the **striatum** and **nucleus accumbens**.
48
How does DA form dimers in nucleus accumbens
With **oxytocin** (oxytocin receptor + D2).
49
Where are most DAergic cell bodies located
In the **substantia nigra** (SN) or **ventral tegmental area** (VTA) of the midbrain.
50
What pathway arises from dopamine neurons in the substantia nigra
The **nigrostriatal pathway**.
51
What does the nigrostriatal pathway target
The **striatum**.
52
What is the nigrostriatal pathway important for
**Motor control**.
53
What pathways arise from dopamine neurons in the VTA
The **mesocortical** and **mesolimbic** pathways.
54
What does the mesolimbic pathway target
The **nucleus accumbens**.
55
What are the mesocortical and mesolimbic pathways involved in
**Reward** **reinforcement** **linking/learning/wanting** (mesocorticolimbic).
56
What is the tuberoinfundibular pathway involved in
Regulation of **hormone release**.
57
What DA receptors are involved in the striatum's ‘Go’ and ‘No Go’ pathways for motor control
**D1** and **D2 receptors**.
58
What are some key function areas of dopamine
**Motor control** **Liking/learning/wanting** and **Regulation of hormone release**.
59
How does DA regulate hormone release
Suppresses **prolactin** and **GnRH** and increases **GH**.
60
What are some peripheral effects of DA
Increases **metabolism** promotes **GI motility** **insulin production** and **vasodilation**.
61
How can DA be released peripherally
In an **endocrine fashion** with systemic effects or have **paracrine effects**.
62
What is Parkinson’s Disease
Loss of **DA neurons in the substantia nigra pars compacta**.
63
What intraneuronal aggregates are associated with Parkinson's
**Lewy bodies** enriched in **α-synuclein**.
64
What are the motor symptoms of Parkinson's
**Bradykinesia** **resting tremor** **rigidity** **postural instability**.
65
What is Huntington’s Disease
Loss of **D1 & D2 expressing neurons in striatum**.
66
Where is the most profound neurodegeneration in Huntington's
In the **caudate** and **putamen**.
67
What is central to symptoms in Huntington's
Dysfunctional **dopamine signalling**.
68
What characterizes early stage Huntington's movements
**Hyperkinetic movements**.
69
What characterizes late stage Huntington's movements
**Hypokinesia**.
70
How can dopamine and glutamate signalling interact in Huntington's
They can **synergistically enhance toxicity** through **D1 receptor activation**.
71
What is Schizophrenia linked to in terms of DA pathways
**Hyperactive mesolimbic** & **hypoactive mesocortical** pathways.
72
What dopamine receptor alteration is seen in schizophrenia patients
**High levels of D2 dopamine receptor density**.
73
What are the symptoms of schizophrenia
**Positive** (hallucinations disorganized speech/behaviour) **negative** (impaired motivation social withdrawal) and **cognitive** (memory dysfunctions) symptoms.
74
What is ADHD linked to in the DA system
**Mutations in DAT D4 & D5**.
75
What is a target of anti-hyperactivity drugs like amphetamine
**DAT**.
76
What characterizes ADHD
**Inattention** **impulsiveness** **excessive motor activity** and **hyperactivity**.
77
What DA receptor change is seen in addiction
**Reduced D2 expression** **increased D1**.
78
Where are low levels of D2 receptors seen in addiction
In **striatal areas**.
79
What evidence links synaptic alterations in mesolimbic pathways to addiction
Strong evidence links them to **drug and food addiction**.
80
What characterizes addiction
**Compulsive drug intake** **inability to restrict intake** and **withdrawal syndrome**.
81
What drug is used to treat Parkinson's Disease
**L-DOPA**.
82
What adjunct is sometimes used with L-DOPA and why
**Carbidopa** to prevent peripheral D2 signalling and nausea.
83
What is a target of stimulants used to treat ADHD
**DAT**.
84
What other drug is used to treat Parkinson's
**Bromocriptine**.
85
How is noradrenaline (NA) synthesised
In **synaptic vesicles**.
86
What enzyme turns dopamine into noradrenaline
**DBH** (dopamine beta-hydroxylase).
87
Where does adrenaline (A) biosynthesis occur
Partly **outside synaptic vesicles**.
88
How is NA turned into adrenaline
By **PNMT** (phenylethanolamine N-methyltransferase).
89
What does PNMT do
Adds a **methane group** to noradrenaline.
90
How is adrenaline stored for release
Pumped back into **vesicles** for release via exocytosis.
91
How is the action of noradrenaline and adrenaline terminated
The same way as for dopamine by **reuptake** and **degradation**.
92
What is the specific transporter for NA
**NET**.
93
What are the postsynaptic noradrenergic receptors
**β1 β2 β3** and **α1**.
94
Are the postsynaptic noradrenergic receptors excitatory or inhibitory
They are all **excitatory**.
95
What is the type of presynaptic adrenoceptor
**α2 autoreceptor**.
96
Is the presynaptic α2 autoreceptor excitatory or inhibitory
**Inhibitory**.
97
Where are noradrenergic cell bodies located
In the **locus coeruleus** (LC).
98
What is the nature of projections from the LC
They are **diffuse** reaching the entire cortical mantle diencephalon and cerebellum.
99
What are some key function areas of the adrenergic system
**Autonomic effects** (Sympathetic NS) **Endocrine effects** (Adrenal glands) **Central pathways** (Learning and memory Attention).
100
Does NA suppress or enhance pain
NA can **suppress pain**.
101
What neurodegenerative disease is linked to adrenergic dysfunction
**Parkinson’s disease**.
102
What role does neuronal loss from LC play in Parkinson's
It plays a **role in pathogenesis**.
103
What is necessary in animal models to elicit parkinsonism related to NA
Neuronal loss from LC is **necessary**.
104
What is linked to NA depletion
**Depression**.
105
What is the effect of augmenting NA on depression
It **protects against it**.
106
What is linked to relapse in drug addiction regarding the adrenergic system
**Stress** linked to relapse.
107
What is the effect of blocking NA signalling on relapse
It **prevents relapse**.
108
What autonomic issue is linked to adrenergic dysfunction
**Autonomic dysfunction** like excessive sympathetic signalling or loss of sympathetic tone.
109
What can increased NA signalling result in
**Health issues**.
110
What drugs affect the noradrenergic system
**NRIs** **Prazosin** **Yohimbine** **Clonidine** **Propranolol**.
111
What are NRIs used to treat
**Depression**.
112
What is Prazosin used to treat
**PTSD**.
113
What are Clonidine and Propranolol used to treat
**High B.P.**.
114
What is the starting point for serotonin biosynthesis
**Tryptophan**.
115
What turns Tryptophan into 5-HTP (5-hydroxytryptophan)
The removal of a hydroxyl group by **tryptophan hydroxylase**.
116
What turns 5-HTP into serotonin
**5-HTP decarboxylase** (AADC) removes a carboxyl group.
117
How is serotonin removed from the synapse
By **reuptake** or **degradation**.
118
What is the specific transporter for 5-HT
**SERT**.
119
Are there many types of 5-HT Receptors
**Yes** including 5HT1A-F/5 5HT2A-C 5HT3 5HT4/6/7.
120
What G proteins do 5HT1A-F/5 receptors couple to
**αi** (inhibitory).
121
What is the effect of αi coupling for 5HT1A-F/5 receptors
Affecting **AC** (inhibitory).
122
What G proteins do 5HT2A-C receptors couple to
**αq** (excitatory).
123
What is the effect of αq coupling for 5HT2A-C receptors
Affecting **PLC-β** (excitatory).
124
What G proteins do 5HT4/6/7 receptors couple to
**αs** (excitatory).
125
What is the effect of αs coupling for 5HT4/6/7 receptors
Affecting **AC** (excitatory).
126
What is the only ionotropic receptor acted on by a monoamine
**5HT3**.
127
What type of receptor is 5HT3
A **ligand-gated ion channel**.
128
What ions is the 5HT3 receptor permeable to
**Ca2+** and **Na+**.
129
Where are 5HT1/5 receptors found and what do they do
Found **presynaptically** and mediate **suppression**.
130
Where are 5HT3 receptors usually found
Usually at **extrasynaptic sites** rarely in postsynaptic density.
131
What is the function of 5HT3 receptors at extrasynaptic sites
Involved in **bulk release** and have a **modulatory function**.
132
What are some 5-HT receptors targets for
**Psychotropic drugs**.
133
Where are serotonergic cell bodies located
In midline **raphe nuclei** throughout the brain stem.
134
Where do Caudal raphe nuclei project to
The **spinal cord**.
135
What are projections from Caudal raphe nuclei important for
The **modulation of afferent pain signals**.
136
Where do Rostral raphe nuclei project to
Just about **everywhere else**.
137
What neurotransmitter do most serotonergic neurons co-release
**Glutamate** (most also express vGlut3).
138
Can 5-HT have both positive and negative effects on the same system/organ
**Yes**.
139
What is a key function area of the serotonergic system
**Mood regulation**.
140
How do drugs targeting 5-HTRs affect mood
Many **affect mood**.
141
What types of 5-HT drugs can be antidepressants
**5-HT1 agonists** and **antagonists**.
142
What 5-HT drugs produce hyperphagia (increase appetite)
**5-HT1 agonists**.
143
What 5-HT drugs produce hypophagia (decrease appetite)
**5-HT2C/4 agonists**.
144
What 5-HT drugs produce analgesia (pain relief)
**5-HT1 agonists** and **5-HT3/7 antagonists**.
145
What is linked to hypofunction of the 5-HT system
**Depression**.
146
What are symptoms of Serotonin syndrome
**Headache** **nausea** **autonomic symptoms**.
147
What causes Serotonin syndrome
**Excessive SE signalling**.
148
What is the effect of 5-HT2C agonists on compulsive behaviours
They **inhibit** them.
149
How does 5-HT relate to Migraine
5-HT **sensitises the trigeminal nerve**.
150
What can cause anxiety related to the 5-HT system during development
**5-HT depletion** or **KD of 5-HT1ARs**.
151
What drug class is used to treat depression targeting 5-HT
**SSRIs** (Selective Serotonin Reuptake Inhibitors).
152
What drugs are used to treat migraine targeting 5-HT
**Triptans** (5-HT1D agonists).
153
What are atypical neurotransmitters
Neurotransmitters that **deviate from strict criteria** defining classical NTs.
154
What are the strict criteria for classical neurotransmitters
**Synthesis and storage in presynaptic neurons** **Release presynaptically upon stimulation** **Response Mimicry** and **Inactivation**.
155
Which criterion holds across all atypical NTs
**Response Mimicry**.
156
Where are some atypicals synthesized
**Postsynaptically**.
157
How are some atypicals stored
Sometimes **not stored at all**.
158
How are some atypicals eliminated from the cleft
They sometimes just **diffuse away**.
159
What types of atypical neurotransmitters are listed
**Purine transmitters** **Cannabinoids** **Nitric Oxide** and **Neuropeptides**.
160
Where are neuropeptides produced in the cell body
By **ribosomes in the ER**.
161
How does NP production location contrast with classical NTs
Classical NTs are manufactured in the **synaptic terminal**.
162
How are NPs transported to the axon terminal/synapse
They are **transported**.
163
How are NPs processed
**Cleaved/processed from large precursor proteins**.
164
What can differential processing of precursor proteins give rise to
**Multiple active peptides** from one precursor.
165
What is an example of a precursor protein and its resulting peptides
**Proopiomelanocortin (POMC)** processed into ACTH MSH Beta-endorphin.
166
Where are NPs stored
In **large granular vesicles** (LGVs) or **LDCVs**.
167
How does NP storage differ from classical NTs
Classical NTs are stored in **small secretory vesicles**.
168
How are NPs often released
As **co-transmitters with a classical NT**.
169
What Ca2+ requirement is generally needed for NP release
**Higher Ca2+** (high fast firing) compared to classical NTs.
170
What fusion is likely required for LGV exocytosis
**Complete fusion** with the presynaptic membrane.
171
How does LGV fusion differ from classical NT release dynamics
Unlike the '**kiss and run**' dynamics reported for classical NT release.
172
Can NPs be replenished immediately during high activation
**No** there is a finite amount at the terminal.
173
What are the stability and diffusion distance of Neuropeptides
They are **relatively stable** and can diffuse **long distances**.
174
What do NPs regulate that classical NTs typically do not
**Extrasynaptic sites**.
175
How are NPs broken down
By **generic peptidases**.
176
How are neuropeptides generally described
A **broad range of proteinaceous molecules**.
177
What are the effects of neuropeptides
They have **pleiotropic effects** in development reproduction physiology and behaviour.
178
How do neuropeptides exert effects
Through **direct autocrine** or **indirect paracrine signalling**.
179
What cells are targeted by NPs through this signalling
**Neurons** **astrocytes** and **microglia nearby**.
180
How is NP production regulated
Activity and expression of **enzymes in the cleavage/processing pathway** can be regulated.
181
How can synaptic input regulate NP production
By **switching inputs to a neuron**.
182
What is the duration of modulation by neuropeptides when combined with classical NTs
**Prolonged modulation** (seconds to minutes).
183
How does NP modulation speed contrast with classical NTs
Classical NTs provide **fast** (milliseconds) modulation.
184
What roles can neuropeptides play in the nervous system
They can act as **hormones** **neurotransmitters** and **neuromodulators**.
185
Why are neuropeptides considered good candidates for novel drug development
For various **neurological conditions**.
186
What peptides are involved in development
**Nerve Growth Factor** (NGF) **Brain Derived Neurotrophic Factor** (BDNF) and **Oxytocin**.
187
What is the function of NGF
Involved in **neurodevelopment**.
188
What is the function of BDNF
Involved in **development** and **memory** (LTP).
189
What are the time-specific effects of Oxytocin on development
Effects on **early postnatal development**.
190
What peptides are involved in pain
**Substance P** **Endorphins/enkephalins/dynorphin** **Neuropeptide Y** (NPY).
191
What is the role of Substance P in pain
Involved in **nociception** and **pain**.
192
What is the role of Endorphins/enkephalins/dynorphin in pain
They **suppress nociception** and **pain**.
193
What peptides are involved in pleasure
**Orexin** and **Endorphins/enkephalins/dynorphin**.
194
What peptides are involved in feeding behaviour and Appetite
**Orexin** **Galanin** **NPY** **AGrP** **MSH** and **Oxytocin**.
195
What is the general effect of MSH (Melanocyte Stimulating Hormone) on feeding
**Low feeding**.
196
What peptides are involved in Wakefulness
**Orexin**.
197
What peptides are involved in Bonding
**Oxytocin**.
198
What specific bonding is linked to Oxytocin
Between **partners** and **mother and child**.
199
What is the central hub for peptidergic control of feeding
The hypothalamus's **arcuate nucleus**.
200
What neurons control feeding in the arcuate nucleus
**POMC neurons** and **agouti-related peptide (AGrP) neurons**.
201
Where are satiety neurons located and what do they do
In the **Paraventricular Nucleus (PVN)** and they **inhibit feeding behaviour**.
202
When do POMC neurons become active regarding energy levels
When energy levels are **sufficient**.
203
What peptide is produced by active POMC neurons
**α-MSH**.
204
Where does α-MSH bind
To **melanocortin-4-receptors** (MC4Rs).
205
What is the effect of α-MSH binding to MC4Rs
Sends a **satiety signal** that decreases hunger and reduces food intake.
206
How do POMC neurons suppress feeding
By **exciting satiety neurons** via MC4Rs.
207
When are AGrP neurons activated
When the body **needs more energy**.
208
What peptides are released by AGrP neurons
**AGrP** and **NPY**.
209
What is the effect of NPY in the hypothalamus on hunger
It **increases hunger**.
210
How does AGrP inhibit α-MSH action
By **blocking MC4Rs**.
211
What is the mechanism of AGrP antagonism at MC4Rs
It acts as an **antagonist** which helps boost appetite and stimulate feeding.
212
How do AGrP neurons also inhibit satiety neurons
By releasing **GABA** and **NPY**.
213
What classical NTs are released by nociceptors under normal conditions
Mainly **Glu**.
214
What happens to nociceptors when tissue damage occurs
There is a **strong activation**.
215
What substances are released by activated nociceptors in addition to Glu
**Substance P** and **NPY**.
216
What is the effect of this additional release on the postsynaptic cell
Leads to **sustained depolarization**.
217
What is the effect on pain signal propagation and perception
**Increasing pain signal propagation** and **intensifying pain perception**.
218
What receptor does Substance P bind to
**Neurokinin-1** (NK1).
219
What is the nature of the NK1 receptor
It is a **GPCR**.
220
What is a downstream effect of NK1 activation
Activates **PKA**.
221
How does PKA affect AMPA receptors
**Phosphorylates** them increasing their sensitivity to Glu.
222
What is the overall effect of PKA phosphorylation of AMPA receptors in pain signalling
Amplifying the **excitatory response** and enhancing the **pain response**.
223
What triggers PKC activity in pain signalling
**Brain-derived neurotrophic factor** (BDNF) release.
224
How does PKC affect AMPA receptors in pain signalling
**Phosphorylates** them further increasing excitability and responsiveness to Glu.
225
What is the overall effect of PKC phosphorylation of AMPA receptors
Contributing to **pain sensation** and making neurons **more sensitive** to further stimulation.
226
What receptors does NGF bind to on the presynaptic terminal
**TrkA** and **p75**.
227
What is the effect of NGF binding on the presynaptic terminal
Increases **excitability**.
228
What is the effect of increased excitability of the presynaptic terminal
Leading to a **greater release of NPs** including Substance P.
229
What are other effects of NGF binding to its receptors
Leads to **internalization** promoting **synthesis and release of more NPs**.
230
What do endogenous opioids provide
**Pain relief**.
231
What receptors do endogenous opioids bind to on nociceptive neurons
**μ-opioid receptors**.
232
What is the effect of μ-opioid receptor activation on ion conductance
Increases **K+ conductance**.
233
What is the effect of increased K+ conductance
Which **hyperpolarizes the neuron**.
234
What is the result of hyperpolarization
Reduces **excitability**.
235
What is the overall effect of endogenous opioid action on pain signals
Pain signals are **suppressed** leading to analgesic effects.
236
Why are peptide systems tricky therapeutic targets
**Low oral availability** **Poor BBB penetrance** and **Quick breakdown in the periphery**.
237
Why do endogenous opioids have low oral availability
They are **broken down by peptidases** in the digestive tract.
238
Why do peptides have poor BBB penetrance
Due to their **large size** and **charged nature**.
239
What method uses antibodies to reduce peptide transmission
Antibodies like **Anti-NGF** (Tanezumab).
240
How does Anti-NGF (Tanezumab) act in pain treatment
It **removes excess NGF** in the periphery.
241
What method uses non-peptide drugs centrally
Stimulate or block **peptide receptors**.
242
What is an example of a non-peptide drug used for pain
Synthetic opioids like **morphine**.
243
What is the main psychoactive component of cannabis
**Δ9-Tetrahydrocannabinol** (THC).
244
When was THC identified
In **1964**.
245
What are the endogenous agonists (ligands) of Cannabinoid Receptors (CBRs)
**Anandamide** (AEA; N-arachidonoyl-ethanolamine) and **2-arachidonoylglycerol** (2-AG).
246
What are AEA and 2-AG derivatives of
**Arachidonic acid**.
247
How does 2-AG act as an agonist
It is a **full agonist** but low agonist.
248
How does Anandamide act as an agonist
It is a **partial agonist** with higher affinity.
249
Where are endocannabinoids released from
**Postsynaptically**.
250
What is the direction of EC signalling
**Retrograde signalling** (from postsynaptic cell back to presynaptic neuron).
251
Are ECs stored in vesicles
**No**.
252
How are ECs produced
**On demand** in a Ca2+-dependent manner.
253
Does EC production require an action potential
Production is a result of an action potential but **does not require** an action potential itself.
254
What happens to reduced ECs after postsynaptic release
They can act on **adjacent terminals** too.
255
What is the physical nature of ECs
They are **uncharged hydrophobic** (lipids).
256
Can ECs diffuse freely like other neurotransmitters
**No** due to their lipid nature.
257
Is EC transport and uptake fully understood
**No** it is not fully understood.
258
What is the rate-limiting step in EC synthesis
The formation of **NAPE** (for AEA) and **DAG** (for 2-AG).
259
What is required for this rate-limiting step
It is **Ca2+-sensitive**.
260
What enzyme catalyzes AEA synthesis from NAPE
**NAPE-specific phospholipase D** (NAPE-PLD) or other routes.
261
What enzyme produces 2-AG from diacylglycerol (DAG)
**DAG lipase** (DAGL) α or β.
262
What DAGL isoform generates most synaptic 2-AG in adult brain
**DAGLα**.
263
Do AEA and 2-AG synthesis transport and inactivation differ
**Yes**.
264
How are ECs degraded
Through **hydrolysis** and/or **oxidation** once taken up by cells.
265
What enzyme degrades AEA
**Fatty acid amide hydrolase** (FAAH).
266
What are the products of AEA degradation
**Arachidonic acid** and **ethanolamine**.
267
What enzyme mostly hydrolyses 2-AG
**Monoacylglycerol lipase** (MAGL).
268
What are the products of 2-AG hydrolysis by MAGL
**Arachidonic acid** and **glycerol**.
269
What is required for termination of 2-AG signalling
**Degradation by MAGL**.
270
When were the CB1 and CB2 receptors identified/cloned
**CB1 in 1990** and **CB2 in 1993**.
271
Where are CBRs generally found
**Presynaptically**.
272
What typical pathway do both CB1 and CB2 receptors act via
The **Gi pathway**.
273
What is the effect of activating the Gi pathway for CBRs
Inhibiting **adenylyl cyclase** (AC).
274
What other pathways has CB1 been shown to signal using
The **Gs** and **β-arrestin pathway**.
275
How do CBRs regulate ion channel function
They regulate it.
276
What specific ion channels are regulated by CBRs
Including **positive modulation of K+ leak channels** and **inhibition of Ca2+ channels**.
277
What is an effect of CBR regulation of Ca2+ channels
Reducing **presynaptic Ca2+ influx**.
278
What are further sites of action for Cannabinoids
Including **TRPV1Rs**.
279
What activates TRPV1 and what is its role
**AEA** activates TRPV1 which has a significant role in **synaptic transmission** and **pain regulation**.
280
Where does the full-length CB1R dominate
In the **brain** and **skeletal muscle**.
281
Where is the CB1Rb isoform more expressed
In **liver** and **pancreatic islet cells**.
282
What is CB1Rb involved in
**Metabolism**.
283
How many isoforms of CB2R have been identified in humans
**Two**.
284
Where is one CB2R isoform predominantly found
In **testis** (lower levels in brain reward regions).
285
Where is the other CB2R isoform mainly found
In **spleen** (lower levels in brain).
286
What is Cannabidiol (CBD)
A **negative allosteric modulator of CB1** and an **indirect antagonist of CBRs**.
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How is CBD used therapeutically
In the treatment of **epilepsy** and modulation of **chronic pain**.
288
How does endocannabinoid-mediated retrograde signalling often start
With **2-AG production** in response to increased intracellular **Ca2+ concentration** and/or **activated Gq/11-coupled receptors**.
289
Where is 2-AG released after production
Into the **extracellular space**.
290
What receptor does 2-AG bind to
The **presynaptic CB1R**.
291
What is the effect of activated presynaptic CB1R
Suppresses the **release of neurotransmitter**.
292
What are the two ways activated presynaptic CB1R suppresses neurotransmitter release
1) By **inhibiting voltage-gated Ca2+ channels** (reducing presynaptic Ca2+ influx) and 2) By **inhibiting adenylyl cyclase (AC)** and the subsequent cAMP/PKA pathway.
293
What is the cAMP/PKA pathway involved in
**LTD** (Long-Term Depression).
294
How is signalling terminated for 2-AG
By its **degradation**.
295
What enzyme is involved in 2-AG degradation for signalling termination
**MAGL**.
296
Where does 2-AG degradation occur
In **selective synaptic terminals** and **glial cells**.
297
How do ECs act at CB1Rs
To **suppress synaptic transmission** through multiple mechanisms.
298
Are EC suppression mechanisms dependent on synaptic nature or transmission duration
**No** they are independent.
299
What role do ECs play in synaptic plasticity
They are involved in **short- and long-term synaptic plasticity**.
300
Are the central roles of CB2Rs well understood
**Less well understood** than CB1Rs.
301
What are some functions of the EC system
Role in **memory** **appetite control** **pain perception** and **gastric motility**.
302
What dysfunctions are linked to abnormal EC system function
**Schizophrenia** **epilepsy** **MS** and **neurodegeneration**.
303
How are Gasotransmitters described
**Volatile signalling molecules**.
304
How do gasotransmitters differ from classical transmitters in storage
They are **not stored** (in vesicles).
305
How do gasotransmitters differ from classical transmitters in release
They are **not actively released** (in the classical sense).
306
How do gasotransmitters differ from classical transmitters in elimination
They are **not actively eliminated**.
307
When are gasotransmitters produced
In an **activity-dependent fashion**.
308
How do gasotransmitters diffuse across cell membranes
They **diffuse** due to their gaseous and non-polar nature.
309
What is an implication of this diffusion property
It allows them to influence target cells **without requiring vesicular storage or synaptic release**.
310
What are the possible actions of gasotransmitters
Can have **anterograde** and **retrograde action**.
311
What are examples of Gasotransmitters
**Nitric Oxide** (NO) **Carbon monoxide** (CO) **hydrogen sulphide** and **ammonia**.
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Which gasotransmitter is best characterized
**Nitric Oxide** (NO).
313
Is Nitrous oxide the same as Nitric oxide
**No** it is different.
314
How is NO molecule described
A **small unstable molecule** with a very short half-life.
315
What properties make NO suitable for signalling
Small size instability and short half-life make it suitable for **localized and transient signalling**.
316
How is NO produced intracellularly
By converting **L-arginine to L-citrulline**.
317
What enzyme catalyzes NO synthesis
**Nitric oxide synthase** (NOS).
318
What is required for NO synthesis
It is **Ca2+-dependent**.
319
How is NO synthesis typically activated
By **increased intracellular Ca2+ levels**.
320
What mediates increased intracellular Ca2+ for NO synthesis
**Voltage-gated calcium channels** (VGCC) or **receptor activation** (like NMDARs).
321
What does Ca2+ bind to for NOS activation
**calmodulin** (CaM).
322
What types of NOS are activated by CaM
**neuronal NOS** (nNOS) and **endothelial NOS** (eNOS).
323
Where is nNOS abundant
In the **brain** higher in hippocampus and cerebellum.
324
Where is eNOS located
In the **endothelium of blood vessels**.
325
What is the function of eNOS
Produces NO as part of **blood flow regulation**.
326
What is the target of NO at physiological concentrations
**Guanylyl cyclase** (GC) in target cells.
327
What process is catalysed by GC
Conversion of **GTP to cGMP**.
328
What does cGMP activate
**Protein kinase G** (PKG).
329
What does PKG modulate
Various **cellular targets** including ion channels.
330
What are examples of cellular functions modulated by PKG
**Vascular relaxation** and **neuromodulation**.
331
What is the primary method of NO elimination
**Diffusion**.
332
What can NO form at elevated concentrations
**Peroxynitrite** (ONOO-).
333
What are the properties of peroxynitrite
It is **highly reactive**.
334
What damage is caused by peroxynitrite
It can damage **proteins** **lipids** and **DNA**.
335
What is the significance of peroxynitrite in diseases
It is significant in **neurodegenerative** and **cardiovascular diseases**.
336
What are some functions of NO
**Dilating blood vessels** **neuromodulation** **paracrine cell signalling** **mitochondrial function**.
337
What is the role of excessive NO production in stroke/excitotoxicity
It **contributes to neuronal damage**.
338
How does high NO exacerbate oxidative stress
Leading to **cell death**.
339
What role does NO play in triggering puberty
It **affects GnRH release** from the hypothalamus.
340
What is NO's role in Plasticity learning & memory
It **facilitates LTP** in the hippocampus and **modulates NT release and receptor sensitivity**.
341
How does NO support memory storage and retrieval
By **modulating NT release and receptor sensitivity**.
342
What is NO's role in Endocrine control
Involved in **regulating hormonal pathways**.
343
What pituitary hormones are affected by NO
**Oxytocin** and **vasopressin**.
344
What is the impact of NO on stress responses and reproductive function
It **impacts** them.
345
What is Oxytocin linked to
**Pair bonding** and **sexual satisfaction**.
346
What does Vasopressin contribute to
**Territorial** and **aggressive behaviours** potentially related to mating.
347
What are some functions of CO
Regulates **circadian rhythms**.
348
How does CO regulate circadian rhythms
By influencing **clock gene expression**.
349
What processes are affected by circadian rhythm regulation by CO
**Sleep** **metabolism** etc..
