Module B-06 Flashcards
1
Q
Describe life cycle of small molecule transmitters
A
- Synthetic enzymes manufactured in rough ER
- Enzymes modified in Golgi apparatus
- Enzymes transported to terminals
- Precursors taken up to interact with enzymes released from vesicles
- Transmitters loaded into vesicles
a. Most enter clear-core vesicles
b. Serotonin and Norepi enter dense-core vesicles - Transmitters released through exocytosis
- Transmitters may interact with receptors
- Transmitters may be taken up
- Transmitters may be metabolized
- Metabolites may be taken up
2
Q
Describe Life Cycle of Neuroactive Peptides
A
- Pre-propeptides and cleaving enzymes synthesized in rough ER
- Pre-propeptides and cleaving enzymes packed in dense-core vesicles in smooth ER
- Dense-core vesicles transported towards terminals
- Cleavage sometimes yields many neuroactive peptide transmitters
- Peptides released through exocytosis (often co-released with a small molecule transmitter)
- Peptides may interact with receptors
- Peptides may diffuse away from synapse, undergoing enzymatic degradation without uptake
3
Q
_________ not _________dictate excitatory versus inhibitory effects on cell
A
Receptors; Transmitters
4
Q
Describe synthesis of Acetylcholine
A
- Glucose enters cell through facilitated diffusion
- Cytoplasmic glycolysis generates pyruvate
- Pyruvate enters mitochondria and donates acetyl group to coenzyme-A, yielding acetyl coenzyme-A, which returns to cytoplasm
- Choline retrieved from the synapse interacts with acetyl coenzyme-A in presence of ACh transferase to yield ACh
- ACh enters vesicles
5
Q
Describe degradation of Ach
A
ACh esterase hydrolyzes ACh (resultant choline taken up for re-use)
6
Q
Cholinergic neurons of the rostral pons (Dorsolateral Pontine tegmental constellation of cholinergic neurons) project to
A
brainstem, thalamus, hypothalamus, cerebellum, basal ganglia and other cholinergic cells of the basal forebrain.
7
Q
Cholinergic neurons of the basal forebrain( including basal nucleus of Meynert) project to the
A
cortex,
hippocampus
amygdala
8
Q
Preganglionic autonomic nuclei (cholinergic) of the brainstem and spinal cord
A
projecting to peripheral postganglionic autonomic neurons
9
Q
Peripheral cholinergic neurons
A
- Lower motor neurons give rise to axons that exit the central nervous system en route to somatic muscle
- Preganglionic autonomic neurons dwell just medial to the sulcus limitans in the brainstem and select levels of the thoracic, lumbar and sacral spinal cord
a. Typically follow cranial nerves or ventral spinal nerves to release ACh onto either postganglionic neurons or adrenal chromaffin cells - Postganglionic neurons innervate visceral targets
a. All parasympathetic postganglionic and some sympathetic postganglionic neurons also release ACh
10
Q
An ionotropic receptor for ACh is called _________
A
nicotinic receptor
11
Q
metabotropic ACh receptor are called _________
A
Muscarinic receptors
12
Q
Number of muscarinic receptors
A
five subtypes of metabotropic ACh receptor
(M1 – M5) some excitatory , some inhibitory
13
Q
_________ and __________ amino acids are main central excitatory transmitters
A
Glutamate ; Aspartate
14
Q
Glutamate exerts inhibitory effects in ________ of CNS
A
Retina
15
Q
2 methods of Glutamate synthesis
A
1) Krebs cycle
2) Glutamate recycling
16
Q
Describe Krebs cycle synthesis of Glutamate
A
- Glucose enters neuron by facilitated diffusion
- Intracellular glucose metabolized via Krebs cycle
- Alpha-oxoglutarate transaminase yields glutamate
17
Q
Describe Glutamate recycling
A
Astrocytes
1. Astrocytic glutamate transporters take up extracellular glutamate
2. Glutamine synthetase metabolizes glutamate to form glutamine in astrocytes
3. Glutamine exits astrocytes and enters neurons through
glutamine transporters
4. Intraneuronal glutaminase converts glutamine to
glutamate for reloading into vesicles
Nerve Terminal
1. Terminal glutamate transporters take up extracellular glutamate
2. Glutamate taken up by neuronal terminals is also
subject to vesicular reloading
18
Q
Locations of Glutamatergic neurons
A
-centrally ubiquitous
-Many peripheral sensory axons projecting into the
brainstem or spinal cord
-numerous special sensory neurons release glutamate despite lacking axons
19
Q
Describe synthesis of Aspartate
A
transamination of oxaloacetate
20
Q
Removal of Aspartate
A
-synaptic aspartate may use the glutamate uptake transporter, also known as the glutmate-aspartate transporter
21
Q
Location of Aspartergic neurons
A
- interneurons (excitatory role) in the spinal ventral horn.
- some cerebellar efferents
22
Q
Types of Ionotropic Glutamate receptors
A
AMPA/Quisqualate
Kainate (Kanic acid)
NMDA
23
Q
effects of AMPA/Quisqualate receptors (nGlut)
A
Agonists provoke the influx of Na+ and the efflux of K+.
24
Q
effects of Kainate receptors (nGlut)
A
Agonists provoke the influx of Na+ and the efflux of K+.
25
effects of NMDA receptors (nGlut)
1. Agonists open a central pore, provided that glycine also occupies a strychnine-insensitive binding site.
2. With sufficient depolarization of the membrane (e.g., through the actions of other glutamate receptors), Mg++ exits, thus permitting the influx of Ca++ and Na+
and the efflux of K+
3. NMDA receptor-dependent ionic fluxes contribute relatively little to changes in membrane potential but promote calcium dependent processes (e.g., enzyme activity)
26
Types of Metabotropic Glutamate receptors
There are eight known mGluRs that can be divided into three Groups.
1. Group I mGLURs typically excite.
2. Group II mGLURs typically inhibit.
3. Group III mGluRs typically inhibit.
27
_______ and ________ are inhibitory amino acids
GABA; Glycine
28
Describe synthesis of GABA
1. Glutaminase converts glutamine to glutamate.
2. Glutamic acid decarboxylase converts glutamate to GABA.
3. GABA is transported loaded into vesicles.
29
Describe GABA removal
1. After release, GABA transporters take up GABA for reuse.
2. Glia take up GABA, where GABA transaminase degrades
GABA to form glutamate.
3. Glutamine synthetase then converts glutamate to glutamine.
4. Glutamine may be returned to neurons for re-synthesis of glutamate.
30
Location of GABAergic neurons
```
– Small GABAergic neurons are
ubiquitous modulators
– Longer GABAergic pathways
arise from varied nuclei
• Striatum >> substantia nigra
• Substantia nigra >> thalamus
• Medial vestibular nuclei >> spinal cord
• Cerebellar cortex >> deep cerebellar nuclei
```
31
2 types of GABA receptors
GABAa - ionotropic (permeable to Cl-)
| GABAb- metabotropic (G-protein-mediated coupling to calcium and potassium channels)
32
Effects of GABA a receptor
limit excitability of neurons by holding membrane potentials near resting values
33
Drugs that act on GABA a receptors and their effects
Allosteric binding sites for benzodiazepines and barbiturates
• Occupation increases GABA-dependent Cl- currents
34
Effect of GABA b receptors
-reduces excitability by decreasing Ca++ influx or by increasing K+ efflux
35
What type of synapses have GABAb receptors
axoaxonic synapses featuring GABAb receptors, reduce Ca++ influx and thus limit
the exocytotic release of transmitter
36
Synthesis of Glycine
1. Glycolysis of glucose yields 3-phosphoglycerate and subsequently serine.
2. Serine transhydroxymethylase folate-dependently converts serine to
glycine.
37
Removal of Glycine
Membrane-spanning transporters take up synaptic glycine
38
Location of Glycinergic neurons
small, exerting local inhibitory actions in the retina
| and the gray matter of the braintem and spinal cord.
39
Effect of Glycinergic receptors
structural and functional similarities to GABAa
| receptors, likewise acting as ligand-gated Clchannels
40
Glycinergic receptors can be blocked by
strychnine (causes rigid muscles)
41
Describe Dopamine synthesis
1. Tyrosine is actively transported into catecholaminergic neurons
2. Tyrosine hydroxylase converts tyrosine to dopa
3. Dopa decarboxylase converts dopa to dopamine (DA)
4. DA is loaded into vesicles for release
42
Describe Dopamine removal
1) Presynaptic cell
Reuptake-1 actively transports DA into the
presynaptic neuron
a. Some DA is reloaded into vesicles
b. Remaining DA is metabolized by MAO
2) Postsynaptic cell
Reuptake-2 actively transports DA into postsynaptic
cell for metabolism by COMT
3) Liver
Remaining synaptic DA diffuses and is absorbed by
blood for peripheral metabolism (uses MAO and COMT)
43
Location of Dopaminergic neurons
1. The substantia nigra pars compacta projects via the
nigrostriatal pathway to the caudate and putamen to
regulate motor function
2. The ventral tegmental area, situated medial to the
substantia nigra, projects to:
a. Prefrontal cortex (mesocortical pathway)
b. Nucleus accumbens and limbic structures
(mesolimbic pathway)
3. The hypothalamic arcuate nucleus projects to:
a. Hypothalamic median eminence for dumping of
DA into hypophyseal portal system for
suppressing the release of prolactin
44
2 groups of Dopaminergic metabotropic receptors
D1-like (D1, D5)
| D2-like (D2 , D3, D4)
45
Effect of D1 like receptors
increase in production of cAMP
46
Effect of D2 like receptors
decrease production of cAMP
47
Synthesis of Norepinephrine
1) Dopamine is loaded into vesicles with dopamine-β-hydroxylase
2) converts dopamine to norepinephrine
48
Removal of Norepinephrine
same as Dopamine removal
49
Location of Dopaminergic nuclei
1. The locus coeruleus (blue place) projects to the diencephalon, limbic system, cerebral lobes and the cerebellum
2. Other clusters of pontomedullary noradrenergic nuclei project to the nucleus of the solitary tract (NTS) and spinal targets
50
Norepinephrine receptors
α and β adrenergic receptors (metabotropic)
51
Effect of α1 and β1 receptors
excitation through activation of:
- phospholipase C ( α1 )
- adenylate cyclase ( β1 )
52
Effect of α2 and β2 receptors
Both α2 and β2 receptors exert inhibitory effects
| by inactivation of adenylate cyclase
53
Describe Epinephrine synthesis
1. Norepinephrine leaks from vesicles into the cytoplasm
2. Cytoplasmic norepinephrine interacts with phenylethanolamine-Nmethyl-transferase (PNMT) to yield epinephrine
3. Epinephrine is reloaded into vesicles
54
PNMT
phenylethanolamine-Nmethyl-transferase
55
Removal of Epinerphrine
Same as Dopamine and Norepi
56
Location of Epinephrinergic nuclei
1. Small clusters of epinephrinergic cells occupy lateral medullary nuclei.
2. Poorly understood projections extend to the hypothalamus, limbic structures, brainstem and spinal cord
57
Receptors for Epinephrine
α and β adrenergic receptors (metabotropic) same as norepi
58
Which receptor has greater affinity for Epi than Norepi
α1: E ≥ NE
α2: E ≥ NE
β2: E >> NE
59
Which receptor has same affinity for both norepi and epi
β1
60
synthesis of Serotonin (5-HT)
1. Tryptophan hydroxylase converts cytoplasmic tryptophan to 5- hydroxytryptophan
2. Aromatic amino acid decarboxylase converts 5- hydroxy-tryptophan to 5-HT (5-hydrox-tryptamine or 5-HT)
3. 5-HT undergoes active transport into vesicles for release
61
5-HT
5-hydrox-tryptamine
62
Removal of seratonin
1. Synaptic 5-HT can undergo reuptake or metabolism by monoamine oxidase to 5-hydroxyindoleacetyldehyde
2. Aldehyde dehydrogenase then converts 5-hydroxyindoleacetyldehyde to 5-hydroxy-indoleacetic acid for urinary excretion
63
Nuclei of Seratonergic neuron
raphe nuclei that are distributed along the midline of the brainstem.
Mesencephalic and pontine raphe nuclei project to
the thalamus, limbic areas and broader cortical
regions.
Medullary serotonergic cells project within the
medulla and the length of the spinal cord.
64
2 types Seratonin receptors
1) metabotropic- 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, 5-HT7
| 2) ionotropic- 5HT3
65
Synthesis of Histamine
1. Histidine is actively transported into the brain
| 2. Histidine decarboxylase converts histidine to histamine
66
Histamine removal
Histamine is metabolized to organic aldehydes and acids by histamine methyltransferase and diamine oxidase
67
Location of histaminergic nuclei and projections
- hypothalamic tuberomamillary nucleus constitutes the principal aggregation of histamine-producing neurons.
- Histaminergic efferents innervate the cortex, hypothalamus, posterior pituitary, cerebellum, medulla and spinal cord
68
Effect of histamine receptors
- Metabotropic H1 receptors increase excitability by suppressing activity of potassium channels.
- H3 receptors are negatively coupled to adenylate cyclase.
- Subunits of the G-protein also suppress voltage-gated calcium channels to decrease transmitter release.
69
What pathways are opioid peptides part of
central pain-regulating pathways, regulators of emotion, movement, feeding, etc
70
Synthesis of beta endorphin
a. Originates from the pre-propeptide pre-proopiomelanocortin in the
rough endoplasmic reticulum of the anterior and intermediate
pituitary and the arcuate hypothalamic nucleus
b. Within the rough emdoplansmic reticulum, the propeptide
proopiomelanocortin is generated
c. Proopionmelanocortin undergoes packaging in the smooth
endoplasmic reticulum
d. Fast orthograde transport drives vesicles from the hypothalamus to
the periaqueductal grey and noradrenergic nuclei
e. Proteolytic cleaving yields beta-endophin, among other peptides
71
Synthesis of Enkephalin
a. Originate from the pre-propeptide pre-proenkephalin in the rough ER of spinal and caudal bulbar neurons
b. The resultant proenkephalin undergoes packaging and fast orthograde transport
c. Proteolysis yields leu- and met-enkephalin, which are then loaded into dense-core vesicles in preparation for exocytosis
72
Which neurons secrete Tachykinins: Substance P
Small unmyelinated periperhal nociceptors release onto
| neurons contributing to ascending pain pathways,
73
How do Nociceptors that release Substance P effect pain pathway
receive axoaxonic inputs from enkephalinergic neurons
| that mediate aspects of opioiddependent regulation of pain
74
Which aspects of the traditional criteria for neurotransmitters do NO and CO fail
1. Not stored in vesicles
2. Non-exocytotic
3. Inactivation is passive and spontaneous
4. No surface receptors
5. Retrograde transmission possible
75
Describe synthesis of NO
1. Glutamate activates post-synaptic NMDA receptors
2. Ca++ entering through the NMDA-related pore combines with calmodulin to activate cNOS
3. cNOS interacts with L-arginine to yield NO and L-citrulline
4. NO activates guanylate cyclase, promoting synthesis of cGMP in either the NO-expressing cell itself or, after intercellular diffusion, neighboring cells (neurons or glia)
76
Where is Substance P released
Released into spinal dorsal horn and spinal nucleus of
| the trigeminal nerve
77
How is substance P inhibited
by 5-HT and NE, acting through enkephalinergic neurons
78
What receptors do Beta endorphin bind to
Mu opioid receptors
79
What receptors do Enkephalin bind to
delta opioid receptors
80
Which seratonin receptors are inhibitory
5-HT1, 5-HT5
