Neurochemistry > 2023 > Flashcards

2023 Flashcards

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1
Q

Fast axonal transport

A

movement of membranous organelles at rates of 200-400 mm/day along axonal microtubules in both the anterograde (carries synaptic vesicle precursors, large dense core vesicles, elements of the smooth endoplasmic reticulum, protein particles carrying RNAs) and retrograde (delivers components for degradation through fusion with lysosomes and signals that regulate gene expression) directions.

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2
Q

Synaptic vesicle life cycle:

A
  1. Membrane components (transporters) are synthesized in the cell body, then transported via anterograde transport and fused to the plasma membrane.
  2. Synaptic vesicle is created via endocytosis with the proteins attached.
  3. Vesicle is transported to the early endosomes (EE)
  4. Empty vesicles bud off the EE and are loaded with neurotransmitters via active transport.
  5. Packed vesicle is either translocated to a large reserve pool or to the active zone on the plasma membrane (docking)
  6. Neurotransmitters are released to the synaptic cleft when vesicle fuses with the plasma membrane (exocytosis).
  7. Synaptic vesicle is recycled by endocytosis (clathrin) repeat of 2-5.
  8. Eventually some synaptic vesicles will be repackaged into retrograde vesicles for return to the cell body and degradation.
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3
Q

Canonical pathway for neurotransmitter release and recycling

A
  1. Neurotransmitter is synthesized in the cytoplasm and then packed into the synaptic vesicles via vesicular transporters.
  2. Synaptic vesicle with the transmitters is translocated to the active zone.
  3. The vesicle docks on the active zone (SNARE proteins).
  4. Vesicle is being primed (ATP)
  5. Ca ion efflux into the neuron leads to vesicle fusion with the plasma membrane and exocytosis – release of neurotransmitters.
  6. Endocytosis of the empty vesicle guided by clathrins.
  7. Loss of clathrins and active transport facilitating ATPase insertion.
  8. The vesicle fuses with the early endosome.
  9. Vesicle buds of the EE and is reused again.
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4
Q

Kiss and run

A
  1. Neurotransmitter uptake
  2. Translocation to the active zone (SNARE)
  3. Docking on the active zone
  4. Priming
  5. Ca initiated NT release (exocytosis)
  6. Clathrin guided endocytosis
  7. Loss of clathrins and addition of ATPase
  8. The vesicle is loaded with neurotransmitters again
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5
Q

kiss and stay

A
  1. Neurotransmitter uptake
  2. Translocation to the active zone (SNARE)
  3. Docking on the active zone
  4. Priming
  5. Ca initiated NT release (exocytosis)
  6. Clathrin guided endocytosis
  7. Loss of clathrins
  8. Vesicle doesn’t leave the active zone, docks and is loaded with NT, is primed again, releases NT
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6
Q

Neuropeptide, monoamine vs small neurotransmitter

A

Neuropeptide is synthesized in the cell body and carried via anterograde transport to the release site maturing in the transported vesicle. Neuropeptides are modulatory and no recycling of the neuropeptides, precursors or dense-core vesicles. Can be released from any point in the neuron, requires higher stimulation as is further from Ca efflux site.

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7
Q

Neuropeptide synthesis

A

Synthesized in the cell body as pre-propeptides, if no pre signaling tail attached, packed into dense-core vesicles and transported via anterograde transport. Final form of neuropeptide is achieved after maturation in the vesicles during transport until it reaches the release site.

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8
Q

Transporter types:

A
  1. Ion channels (regulated by voltage, ligand, phosphorylation) – fast transport
  2. Passive transporters – diffusion.
  3. Active transporters – interact with their substrates, energy source coupled.
    a. Primary active transport – ATPases
    b. Secondary or flux coupled transport – symporters, antiporters.
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9
Q

Efficacy

A

ability to initiate change.

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10
Q

ionotropic receptors

A

Ionotropic receptors are composed of multiple subunits each consisting of 4 transmembrane domains. Mediates fast synaptic transmission via substrate binding which elicits ion channel opening and leads to polarization or hyperpolarization of the membrane.

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11
Q

Guanylyl cyclase receptors

A

have a single transmembrane domain. Agonist binding leads to activation of guanylyl cyclase catalytic region. Decrease in cGMP leads to closing of cGMP gated cation channels (visual, olfactory systems).

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12
Q

Tyrosine kinase receptors

A

consist of single transmembrane domain. Agonist binding causes receptor dimerization leading to stimulation of the catalytic region – autophosphorylation. Signaling cascade.

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13
Q

G protein coupled receptors

A

G protein coupled receptors consist of 7 transmembrane domains and activates guanosine triphosphate binding proteins which leads to second messenger cascade (regulation of K and Ca channel conductance, adenylyl cyclase activity, PI-PLC activation and production of IP3.

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14
Q

Acetylcholine in the neuromuscular junction

A

a. ACh is released from the presynaptic neuron
b. ACh binds to ligand-gated Na channel
c. Depolarization of the end-plate membrane
d. Opening of Na voltage gated channels
e. Action potential at the sarcolemma of muscle fiber
f. Contraction

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15
Q
  1. ACh in the autonomic nervous system
A

a. Myelinated efferent preganglionic neurons of the sympathetic and parasympathetic NS synapse on the postganglionic neurons activating nicotinic ACh receptors.
b. Signal travels through the unmyelinated postganglionic neuron which synapses onto the end organ, parasympathetic neuron on muscarinic ACh receptors and the sympathetic neuron releases norepinephrine on adrenoceptors.

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16
Q

ACh in the CNS

A

a. The interneurons in the striatum
b. Basal forebrain cholinergic complex – ascending arousal system (projects to olfactory bulb, cerebral cortex, hippocampus, habenula, amygdala)
c. Pontomesencephalotegmental cholinergic complex – locomotion, sleep, attention, posture (projects to thalamus, tectum, habenula, vta, cerebellum, vestibular and cranial nerve nuclei.

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17
Q

Acetylcholine synthesis

A

Choline + Acetyl CoA → Ach + CoA (by acetyltransferase (ChAT))

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18
Q

ACh degradation

A

ACh + H2O → Choline + Acetate (by acetylcholinesterase (AChE))

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19
Q

ACh cycle

A
  1. Choline transport protein (ChT, Na/Cl symporter) transports Ch into the cytoplasm.
  2. Choline acetyltransferase (ChAT) synthetizes ACh from choline and acetylCoA (also could be synthetized from breaking down phosphatidylcholine).
  3. ACh is uptaken into vesicles via vesicular ACh transporter (VAChT).
  4. ACh is released into the synaptic cleft vie exocytosis.
  5. ACh is broken down into choline and acetate by acetylcholinesterase (AChE).
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20
Q

nACh

A

nACh receptors are composed of pentameric subunits (at least 2 α) crossing the membrane 4 times. α5 subunit influences Ca permeability. At least 2 ACh are required to bind for activation (α β for neurons). In neurons usually present in a ratio of 3α:2β.

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21
Q

mACh receptors

A

mACh receptors composed of one unit consisting of 7 subunits crossing the membrane. Can be both post and presynaptic, in the neuromuscular junction are expressed on the presynaptic neurons as inhibitory autoreceptors. M1, M3, M5 stimulation of phospholipase C (postsynaptic)(cerebral cortex, striatum, thalamus, brainstem) – elevates Ca, M2, M4 – inhibition of AC (post and presynaptic) (cerebral cortex, striatum, hypothalamus) - affects channel activity.

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22
Q

Norepinephrine cell groups

A

(A1-7):
* The dorsal bundle (locus coeruleus) (A4-6)– projects to cerebral cortex, hippocampus, cerebellum, brainstem and spinal cord. Ascending arousal system, vigilance and responsiveness to unexpected stimuli.
* The lateral ventral tegmental fields (A5-7) – project to the spinal cord and hypothalamus. Belong to the reticular formation, modulating autonomic reflexes and pain sensation.
* Medullary group (A1-2) – project to hypothalamus, concerned with autonomic functions.

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23
Q

Dopamine cell groups

A

(A8-17):
* Nigrostriatal pathway (A8,9) – from substantia nigra projects towards striatum for movement initiation, compulsive behaviour, habit formation.
* Mesocorticolimbic pathway (A10) – from VTA to frontal and temporal cortex, the limbic structures of the basal forebrain. Play a role in reward, motivation, emotion and memory.
* Minor cell groups:
o A11 and A13 – in the hypothalamus project to the autonomic areas of lower brainstem and spinal cord – regulation of the sympathetic preganglionic neurons.
o A12,14,15 – components of the endocrine system. Prolactin and gonadotrophin regulation.
o A17 – retina
o A16 – olfactory bulb

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24
Q

Synthesis of catecholamines:

A

Tyrosine -> (TH) L-DOPA -> (DDC) dopamine.
Dopamine -> (DBH) Norepinephrine -> (PNMT) Epinephrine

Tyrosine hydroxylase, dopa-decarboxylase, dopamine β-hydroxylase, PNMT

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25
Catecholamine transporters
DAT, NET (Na, Cl symporter) (12 membrane crossing subunits) VMAT - active transport
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Catecholamine degradation
MAO, COMT (dopamine metabolites DOPAC and HVA) catechol-O-methyltransferase
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Dopamine receptors
All dopamine receptors are metabotropic. D1 activation stimulates (only postsynaptic) AC (cerebral cortex. Striatum, hypothalamus), D2 inhibits AC (post and pre synaptic)(frontal cortex, striatum, hypothalamus, brainstem) – reduces Ca channel opening and membrane depolarization.
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Adrenergic receptors
All adrenergic (NE and adrenaline) receptors are metabotropic. α1 receptors stimulate phospholipase C (post and pre) (cerebral cortex and cerebellum) - , α2 inhibits AC activity (post and pre (autoreceptor)) (hippocampus, thalamus, locus coeruleus) – lower Ca and β receptors stimulate AC (post, pre (facilitatory autoreceptors) (Cerebral cortex, cerebellum, hypothalamus) – weaken the stress on vascular system, minimize tremor.
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Serotoninergic cell groups
(B1-B9): * Dorsal and median raphe nuclei and B9 cell group projects to the cerebral cortex, forebrain – arousal, mood and cognition. o Dorsal raphe (B6-B7) – innervates cerebral cortex, ventral hippocampus, amygdala, striatum. o Median raphe (B5, B8) and B9 – innervates the whole of the forebrain (cerebral cortex, hippocampus, hypothalamus, septum. * Mid-pons to caudal medulla (B1-B4 (all raphe)) – project to the brainstem, motor and autonomic systems, modulates pain, thermoregulation, cardiovascular and breathing.
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Serotonin sythesis
Tryptophan -> (TH) 5-hydroxytryptophan -> (AADC) serotonin
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Serotonin transporters
Serotonin transporter (SERT) in the neuron’s membrane, VMAT vesicular transporters in synaptic vesicles.
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Serotonin degradation
Serotonin degradation by MAO degrades to 5-HIAA
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Serotonin receptors
Serotonin receptor subtypes (Nuclei of limbic system express most 5 HT receptor subtypes): 1. 5-HT1 – inhibition of AC (reduced cAMP and Ca signalling) (post and pre) 2. 5-HT2 – stimulation of phospholipase C (increase in IP3 and DAG levels) (post) 3. 5-HT3 – ligand-gated ionic channel (Ca, Na, K) (membrane depolarization) (post) (not in the cerebral cortex) 4. 5-HT4 – stimulation of AC (post) 5. 5-HT5 – inhibition of AC (post) 6. 5-HT6 – stimulation of AC (post) 7. 5-HT7 – stimulation of AC (post)
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Endocannabinoids
Cannabinoids contain arachidonic acid. 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamide (AEA, anandamide). No cannabinoid pathways, but the largest concentration in basal ganglia and cerebellum, lowest in medulla and pons, also found in peripheral system and immune cells. Transmits noxious stimuli in the spinal cord. Can diffuse through the membrane and signal onto the neighboring cells. Highly local effect, synthetized on demand. Signal through inhibitory G proteins, can trigger long time depression (LTD).
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cannabinoid receptors
CB1 – interaction can modify other receptors (D2, 5HT2A). CB1 widely expressed in CNS, CB2 in immune cells.
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Endocannabinoid synthesis
from postsynaptic membrane phospholipids containing arachidonic acid: o Initiated by activation of a G-coupled receptor leading to phospholipase C (PLC) stimulation – generation of DAG, DAG hydrolysed by DAGL – synthesis of 2-AG. o Elevation of intracellular Ca activates phospholipase D (PLD) - N-arachidonoyl PE (NAPE) hydrolyses to generate anandamide.
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Endocannabinoid cycle:
1) Glutamate release after depolarization. 2) Glutamate activates postsynaptic receptors and causes rise in Ca. 3) Activation of Ca dependent PLC/D, G-coupled PLC and DAGL 4) 2-AG and anandamide synthesis 5) Endocannabinoids activate presynaptic CB1 and CB2 receptors – inhibition of AC, Ca, stimulation of MAPK.
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Degradation of endocannabinoids:
1) Transported by fatty acid binding protein (FABPs). 2) 2-AG degraded by MAGL to arachidonic acid and glycerol. 3) Anandamide is degraded by fatty acid amidohydrolase (FAAH) to arachidonic acid and ethanolamine.
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Glutamate neurons found in
Mostly present in the cerebral cortex and the limbic system in pyramidal neurons. Spiny stellate neurons in IV cortical level, provide interlaminar connections
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Glutamate synthesis
glutamine -> (PaG) glutamate a-ketogluterate -> (A-T) glutamate
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Glutamate transporters
VGLUT, EAAT1 -membrane EAAT2 -astrocytes, nerve terminal EAAT3/4 - presynaptic/postsynaptic neurons EAAT5 - retina
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Glutamate cycle
1) glutamate synthesized from glutamine (PaG) in the presynaptic neuron 2) Glutamate is packaged into the synaptic vesicles via VGLUT. 3) Glutamate is released to the synaptic cleft 4) Glutamate activates postsynaptic AMPA and NDMA receptors 5) Glutamate is re-uptaken by the astrocytes via EAAT2 transporters and by neurons by EAAT3 transporters. 6) Glutamate in astrocytes is converted back to glutamine by glutamine synthetase 7) Glutamate synthesized from glucose -> a-ketogluterate -> (A-T) glutamate 8) glutamate reverted back to a-ketogluterate (GDH)
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Glutamate degradation
glutamate -> (glutamine synthese) glutamine glutamate -> a-ketogluterate (GDH)
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glutamine transporters
SN -glial SA - neuron
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NMDA receptors
1) Glutamate (glycine coagonist) 2) Permeable to Ca 3) Glu1 subunit - glycine binding site 4) Glu2 subunit - glutamate binding site 5) exchange Na/K 6) Mg ion blocking, removed by local depolarization 7) Zn and phosphorylation sites 8) 4 subunits
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AMPA
1) glutamate 2) 4 subunits (1-2 is enough to activate) 3) local depolarization
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metabotropic GLU receptor (mGLUR)
1) glutamate 2) G-coupled 3) mGLUT1 - stimulation of phospholipase C, Ca increase, post/pre, cerebellar and cerebral cortex, hippocampus, thalamus, basal ganglia, brainstem 4) mGLUR2 - inhibition of AC, post/ pre autoreceptors, cerebral cortex and basal ganglia, cerebellar cortex 5) GluR2 subunit required for Ca permeability
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GABA (role)
1000x higher conc than monoamines feedforward an feedback inhibition Basket, chandelier, purkinje cells most non-terminal synapses movement coordination, inhibition of nociception
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GABA synthesis
Glutamate -> (GAD) GABA
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GABA degradation
GABA -> (GABA-T) succinic semialdehyde (SSA) -> (SSADH) succinate (GABA shunt) - decrease in succinyl - CoA
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GABA transporters
GAT-1 - neuronal, dominant GAT-2 GAT-3 - glial BGT-1 VGATs - vesicular
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GABAa receptor
1) pentamer 2) Cl channel 3) benzodiazepines binding site 4) a-b subunit interface - GABA binding site 5) 2 GABA molecules required for activation 6) 19 subunits
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GABAb receptor
1) 2 subunits - B1 and B2 2) B1 - GABA binding site 3) B2 - G-coupled 4) activation of K channels, inhibition of Ca channels 5) regulation of IP3 production
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Glycine (role)
inhibitory NT in spinal cord motor functions mixed GABA/glycine synapses projections cerebellum - brainstem interneurons hippocampus, retina, auditory, sensory systems
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Glycine synthesis
Serine -> (SHMT) glycine
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Glycine transporters
GlyT1 - astrocytes GlyT2 - neurons VGAT (VIAAT) - vesicular
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Glycine degradation
glycine -> (GAD) CO2 + NH4 glutamic acid decarboxylase
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Glycine receptor
1) pentamer 2) 2 glycine molecules required for activation 3) Gly binding site on a-a or a-b interface
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Gas NT
not resent in synaptic vesicles diffuse through the membrane synthesized on demand no specific receptors can act as a retrograde messenger
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Role of NO
1) activates guanylyl cyclase (GC) (increase in cGMP, cGMP dependent kinases) 2) facilitates synaptic vesicle exocytosis 3) LTP, LDP 4) cholinergic/adrenergic signaling regulation (ANS) 5) diffuses rapidly, short lived
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NO synthesis
from L-arginine via Ca activation of NO synthase (NOS) L-arginine + O2 -> (NOS) L-citrulline + NO
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NO degradation
Oxidation reaction NO+O2 -> NO3
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LTP
1) synchronous firing opens NMDA channels leading to Ca efflux 2) Ca efflux triggers a cascade of biochemical events (Ca/calmodulin) 3) Induction phase: activation of kinases activation of NOS 4) Expression phase: (Postsynaptic) kinases phosphorylate AMPAs - increase in response to GLU (more AMPA receptors) (Presynaptic) NO provides feedback to the presynaptic terminal to increase GLU release (Synaptic) in minutes target dendrites grow - increased number of synapses. 5) Depends on NMDA and Ca signaling.
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Homeostatic plasticity
maintains same output, when the input changes modulates synaptic efficacy (nr of receptors for example) strength of individual synapses compensates for other synapses in the neuron
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endogenous opioid ligands
endorphins enkephalins dynorphins endomorphins nociceptin Tyr - Gly - Gly - Phe
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POMC
pro-opiomelanocortin synthesizing neurons found in arcuate nucleus (hypothalamus), nucleus tractus solitarius (brainstem), pituitary. processed to ACTH, aMSH, acetylated b-endorphin
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Neuropeptides and precursors
Synthesized in the endoplasmic reticulum, preprocessed in Golgi Fast axonal transport No transporters Degraded by peptidases into inactive a.a.
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opioid receptors
g-coupled inhibitory AC
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Parkinson's model
80% diminished dopamine in basal ganglia. Diminished dopaminergic input to striatum leads to reduced excitation of motor cortex and not inhibited ACh leading to tremors
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OCD model
increased activity in prefrontal cortex (ACC, OFC) hyperactivity of basal ganglia and thalamus overactivation of limbic structures, reduced serotoninergic signaling from raphe nucleus raised glutamate in CSF
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Parkinson's treatment
Dopamine precursors DDC inhibitors MAO-B inhibitors COMT inhibitors ACh antagonists
72
OCD treatment
Selective serotonin reuptake inhibitors (SSRI) Tricyclic antidepressants augmentation therapy
Neurochemistry
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