L-04 Neurochemistry Ii Amino Acid Neurotransmitters

Front 1

Major excitatory neurotransmitters

Back 1

Glutamate (main)
Aspartate (secondary but acts on all that glutamate acts on)

Front 2

Major inhibitory neurotransmitters

Back 2

GABA (Brain and spinal cord)

Glycine (primarily spinal cord)

Front 3

Glutamate pathways

Back 3

Cortico-cortical pathways

Corticothalamic pathways

Extrapyramidal pathways (related to Parkinsons)

Trisynaptic pathway in hippocampus

Projections between cortex, substantia nigra, subthalamic nucleus, globus pallidus

Front 4

Glutamate neurotransmission

Back 4

1. Presynaptic neuron makes glutamate from glutamine via deamination with glutaminase.

2. Glutamate is stored in vesicle. AP opens VGCCs, leading to fusion of vesicles through SNAREs.

3. Release of glutamate in synaptic cleft

4. Glutamate binds to postsynaptic receptors

5. Termination via reuptake of glutamate primarily into neighboring glial cells.

6. In glial cells, glutamine synthetase converts glutamate to glutamine.

7. Glutamine is extruded from glial cells and moves to presynaptic glutaminergic neurons where process starts again.

Some glutamate transporters in presynaptic cell as well.

Front 5

Ionotropic glutamate receptors

Back 5

Nonselective cation channels (Na+, K+, Ca2+)

NMDA - highly permeable to Ca2+.

AMPA

Kainate

Front 6

Ionotropic glutamate receptor structure

Back 6

5 subunits. Binding site for glutamate is in extracellular domain which consists of N terminus and loop between third and fourth transmembrane domain.

Second transmembrane domain loops back to intracellular - doesn't fully cross membrane.

C terminal is thus intracellular as opposed to extracellular. C terminal is highly amenable to post-translational modifications.

Front 7

Metabotropic glutamate receptors

Back 7

GPCRs, seven transmembrane domains

Glutamate binds to N terminal domain

Intracellular C terminal domain is highly amenable to post-translational modifications

Front 8

Class 1 of metabotropic glutamate receptors

Back 8

mGluR 1 or 5

Signal through Gq - PLC, DAG (PKC), and IP3 (Ca2+)

PKC activates other protein kinases and Ca2+ activates CaMK - leads to downstream effects

Front 9

Beta-arrestin

Back 9

Binds to metabotropic glutamate receptors and signals for them to be internalized to desensitize cell to glutamate.

Front 10

Class 2 and 3 of metabotropic receptors

Back 10

mGluR 2 or 3

mGluR 4, 7, 8

Signal through Gi proteins.

mGluR 2 or 3 leads to inhibition of AC, reduction in PKA, and activation of K+ channel causing efflux of K+ and hyperpolarization (inhibitory response)

Front 11

Glutamate receptor activity presynaptically

Back 11

Binding of glutamate to mGluR 2 or 3

Pre-synaptically decreases activity of voltage-gated Ca2+ channels to dampen activity of glutaminegic presynaptic terminal.

Front 12

AMPA receptor subtypes

Back 12

Cation channels formed by different subunits that come together to form glutamate-gated channel.

Can be calcium-impermeable - has GluA2R (arginine)

Or calcium-permeable - has GluA2Q or neither Q or R subunits.

These subunits can be modified by RNA editing

Front 13

Agonists of AMPA receptor

Back 13

Glutamate (promiscuous)

AMPA

Front 14

Competitive antagonists of AMPA receptor

Back 14

NBQX, CNQX - relevant for research

No clinically relevant antagonists

Front 15

Kainate receptor agonists

Back 15

Kainate, glutamate

Front 16

Kainate receptor competitive antagonists

Back 16

CNQX (inhibits both AMPA and Kainate)

LY - more selective. Interest in producing analogs for treatment of stroke

Front 17

NMDA activation

Back 17

Dependent on co-binding of glycine and glutamate

Glycine alone will not activate NMDA receptors. Glutamate alone can but small activity.

Front 18

NMDA receptor agonists

Back 18

NMDA, glutamate, glycine

Front 19

Main negative regulator of NMDA receptor

Back 19

Mg2+ acts as open channel blocker - binds to Mg2+ binding site within channel and keeps channel inactive.

Front 20

Competitive antagonists of NMDA receptor

Back 20

APV - research use

Front 21

Noncompetitive antagonists of NMDA receptors

Back 21

Mg2+ - binds to site within channel and inactivates

Kynurenic acid

Pb2+

Ifenprodil

Ketamine - anaesthetic

Phencyclidine (PCP) - addiction

Memantine - Alzheimer's

Front 22

Kynurenic acid

Back 22

Antagonist of NMDA receptors

Metabolite of kynurenine pathway, comes from tryptophan. Kynurenine crosses brain blood barrier and is converted to Kynurenic acid by astrocytes.

Competitive with respect to glycine but noncompetitive with respect to glutamate.

Front 23

NMDA activation in normal conditions

Back 23

NMDA receptors are kept in check with lock from Mg2+.

When glutamate released from presynaptic terminal, cannot overload postsynaptic cell with Ca2+ because would lead to cell death.

Thus, NMDA receptors are only activated by simultaneous glutamate and depolarization (via activation of AMPA receptors (which releases Mg2+ block)

Front 24

AMPA

Back 24

AMPA are sensitive to activation by glutamate, depolarize cell and removes Mg2+ block of NMDA

Glutamate and glycine fully activates NMDA receptor.

Front 25

Long-term potentiation, NMDA, AMPA (Early effects)

Back 25

Protein synthesis-independent

As glutamate keeps being releases and NMDA continually activated, flow of Ca2+ through NMDA activates calcium-calmodulin kinase which induces NO synthase and phosphorylates AMPA receptors to more stably activate them. Leads to synthesis of NO in postsynaptic cell.

NO diffuses to presynaptic cell and facilitates further transmitter release. AMPA activation = further depolarization.

Thus, leads to more sustained, strengthened postsynaptic response.

Front 26

Long-term potentiation (later effects)

Back 26

Protein-synthesis dependent

Ca2+ influx through NMDA activates Calcium-calmodulin kinase which stimulates the synthesis and insertion of new AMPA receptions onto the postsynaptic membrane. Further increases synaptic transmission.

Front 27

Long-term potentiation purpose

Back 27

Underlies memory formation in brain

Front 28

Neurodegeneration in Alzheimer's

Back 28

Early stages - not overt or diagnostic

Later stages - Overt changes. Brain size decreases by 10-20% due to loss of neuron.

Front 29

Extrasynaptic vs synaptic NMDA receptors

Back 29

Synaptic NMDA receptors lead to a calcium influx - involved in synaptic plasticity and memory.

Extrasynaptic NMDA receptors lead to calcium influx that signals cell death. Shuts down CREB which promotes neuronal survival.

Possible because synaptic and extrasynaptic receptors are concentrated in different areas of cell.

Front 30

Memantine

Back 30

Alzheimer's drug

Blocks activity of extrasynaptic NMDA receptors to prevent neuronal death.

Not useful for early stages because also blocks synaptic receptors which are involved in cognitive function.

Front 31

GABA

Back 31

Major inhibitory neurotransmitter in brain

Mostly in local circuitry as interneurons which modulate activity of excitatory neurons.

Front 32

GABAergic neurotransmission

Back 32

1. GABA is synthesized from Glutamate using glutamic acid decarboxylase (GAD). Stored in vesicles

2. Action potential -> VGCCs -> fusion of vesicles with presynaptic membrane

3. GABA binds to postsynaptic ionotropic or metabotropic receptor and exert actions.

Front 33

Termination of GABAergic action

Back 33

GABA diffuses from synaptic cleft and is taken up by glial cells or presynaptic axon.

In glia, GABA is converted to glutamate which is converted to glutamine via glutamine synthetase. Glutamine travels to presynaptic neuron.

In presynaptic neuron, glutamine is converted to glutamate by glutaminase, then to GABA by GAD.

Front 34

Excess of glutamate

Back 34

Excess glutamate accumulates in extracellular space and causes overaction of AMPA and NMDA extrasynaptic receptors, causing cell death.

NMDA receptor is coactivated by basal le

Front 35

Ionotropic GABA receptors classifications

Back 35

GABAa and GABAc (Rho type)

GABAa are primary

Rho type GABAc receptor are only in retina

Front 36

GABAa receptor structure

Back 36

Five subunits, each with four transmembrane domains. Second domain serves as pore.

Gating is positively charged so GABAa receptors are permeable to anions like chloride.

Alpha subunit is ligand binding. Gamma subunit has barbiturate/benzodiazepine binding site.

Front 37

GABAa receptor positive allosteric modulators

Back 37

Barbiturates and benzodiazepines

Augment activity of GABA receptor when GABA is present

Binds to gamma subunit.

Used to prevent convulsions by increasing GABAa receptor activity.

Front 38

Non-competitive antagonists of GABAa receptor

Back 38

Picrotoxin

Dieldrin (organochlorine pesticide)

Front 39

Competitive antagonists of GABAa receptor

Back 39

Bicuculline

Front 40

Result of bicuculline, picrotoxin, dieldrin

Back 40

Excitation - proconvulsants

Front 41

Agonists of GABAa receptor

Back 41

GABA

Muscimol

Front 42

Barbiturate and benzodiapene effect on GABAa receptor

Back 42

Barbiturates (phenobarbitals) increase duration of GABA induced channel activation

Benzodiapines increase frequency of GABA-induced channel openings.

Both increase GABAa receptor function

Front 43

Fundamental forms of inhibition in brain

Back 43

1. Feed-forward inhibition - inhibitory neuron is being excited by outside stimulus.

2. Feedback mechanism - cell that is stimulating the interneuron is inhibited by the interneuron.

Front 44

Chloride transporters in brain

Back 44

KCC2 - exports chloride

NKCC1 - imports chloride

Front 45

GABAa receptor action in immature and mature brain

Back 45

Immature brain - NKCC1 is more active, creating higher chloride inside cell. Chloride flows out through active GABAa channel which has a depolarizing (excitatory) effect.

Developedbrain - KCC2 is more active, raising chloride outside cell. Chloride flows in through active GABAa channels which has a hyperpolarizing (inhibitory) effect.

Front 46

GABAb receptor signaling

Back 46

Seven transmembrane domain

Signals through Gi proteins (blocks AC, decreased cAMP, activated voltage-gated K+ and inactivation of voltage-gated Ca2+ -> inhibition of cell)

Front 47

GABAb receptor agonists

Back 47

GABA

Baclogen

Front 48

GABAb receptor antagonists

Back 48

Phaclofen

Front 49

Glycine

Back 49

Major inhibitoryneurotransmitters at spinal cord

Front 50

Renshawl cells

Back 50

Interneurons that synthesize and release glycine. Excited by motor neurons to release glycine which inhibits the activity of motor neurons.

Front 51

Glycine synthesis and storage

Back 51

Synthesized from serine by serine hydroxymethyltransferase. Stores in vesicles and binds to ionotropic receptors (Cl- channels) ONLY - no metabotropic receptors.

Front 52

Glycine receptor agonists

Back 52

Glycine, serine

Front 53

Glycine receptor antagonists

Back 53

Strychnine (rat poison) but not kynurenic acid

Front 54

Hyperekplexia

Back 54

Mutation in glycine receptor alpha 1 subunit

Hyperreflexia

Prolonged response to auditory stimulus