Neurotransmitters and Excitotoxicity

Question 1

Inhibitory post-synaptic potentials

Answer 1

Small, localized hyperpolarizations almost always associated with chloride entry into the cells. The move the cell further from threshold and make AP less likely

Question 2

Excitatory post synaptic potentials

Answer 2

Small, localized depolarizations commonly produced by entrance of sodium and/or calcium into the cell.

Question 3

Summations

Answer 3

Occurs in the post synaptic cell when multiple IPSPs and EPSPs are elicited by different synapses or by repetitive action of the same synapse (temporal or spatial summation). If there are more IPSPs than EPSPs, the cell is inhibited and no AP occurs and visa versa

Question 4

Gs metabotropic receptors

Answer 4

Proteins activate adenylate cyclase which leads to increased production of cAMP from ATP. cAMP activates PKA which phosphorylates downstream targets, either increasing or decreasing activity.

Question 5

Gq metabotropic receptors

Answer 5

Activate phospholipase C, which then creats IP3 (PIP) and DAG
IP3/PIP activates calcium release, or it can work with DAG to activate PKC which will phosphorylate downstream targets.

Question 6

Fast transport

Answer 6

Usually associated with synaptic vesicles containing peptide neurotransmitters which cannot be made or recycled at the pre-synaptic terminal.

Question 7

Slow transport

Answer 7

Used for structural or other components not needed quickly such as mitochondria and synaptobrevin. Also used for protein/chemicals needed at other locations of neurons such as voltage-gated sodium channels which are used at nodes of ranvier, not the pre-synaptic terminal. Fast route is direct route to pre synaptic terminal

Question 8

Excitotoxicity

Answer 8

When something blocks the delivery of oxygen or glucose to the brain, the neurons in the brain will start to depolarize as the ATP levels fall. There is excess activation which allows huge amounts of calcium to enter the post-synaptic cell. This excess calcium leads to activation of enzymes that lead to the production of nitric oxide, damaging the membranes and even triggering apoptosis in the cortex

Question 9

Catecholamines

Answer 9

Includes dopamine, epinephrine, norepinephrine
Synthesized from tyrosine by tyrosine hydroxylase
For epinephrine to be synthesized, its precursor norepinephrine must be released from the vesicle it was made in. Phenylethanolamine-N-methyl-transferase PNMT is then able to convert norepinephrine to epinephrine

Question 10

4 major pathways using dopamine

Answer 10

Substantia niagra- important in controlling voluntary motion, related to Parkinson’s
Mesolimbic- this pathway runs from the ventral tegmental area to the nucleus accumbens. Related to pleasure/reward system
Mesocortical- runs from ventral tegmental area to the cortex, especially the frontal cortex. Crucial to attention and higher levels of consciousness. Damage is associated with alterations in cognition/consciousness. Dysfunction linked to schizophrenia
Tuberinfundibular- runs from hypothalamus to anterior pituitary. Suppresses prolactins release from pituitary

Question 11

Catecholamine receptors

Answer 11

Alpha-1 uses Gq
Alpha-2 uses Gi
Betas use Gs
Dopamine binds its own receptors D1, D2 etc.. and activate Gi proteins

Question 12

Location of serotonergic neurons in CNS

Answer 12

One cluster of neurons in the brain stem known as the midline raphe nuclei

Question 13

Serotonin destruction

Answer 13

Like catecholamines, serotonin is also destroyed by monamine oxidase

Question 14

Location of histaminergic neurons

Answer 14

Very specific nucleus of the posterior hypothalamus known as the tuberomammillary body

Question 15

Histamine destruction

Answer 15

Diamine oxidase degrades histamine

Question 16

Locations of Ach as neurotransmitter in PNS

Answer 16

NMJ
Autonomic preganglionic synapses
Parasympathetic post-ganglionic fibers
Sympathetic post-ganglionic fibers for sweat glands/muscle vasodilators
Amacrine cells in retina

Question 17

Locations of Ach as neurotransmitter in CNS

Answer 17

Striatum (motor control)
Brainstem arousal system
-the circuit involving the peduculopontine tegmental and laterodorsal pontine nuclei
-also the basal forebrain arousal system (ventral output from reticular activating system)
-producing arousal (non-specific increase in cortical activity produced by sensory info arriving at brainstem arousal systems)

Question 18

Synthesis of acetylcholine done by ___, then transferred into vesicle by

Answer 18

Caholine acetyltransferase

Vesicular acetycholine transporter protein VAchT

Question 19

Ach destruction

Answer 19

True cholinesterase on post synaptic cell membrane
Pseudocholinesterase found in blood and acts on other choline esters
Broken into acetate and choline, choline is taken up by presynaptic cell for recycling

Question 20

Atropine

Answer 20

Blocks muscarinic cholinergic receptors

Question 21

M1-M5 location and effect

Answer 21

M1- post ganglionic neurons of ANS, broad distribution in CNS. Gq protein leads to increased IP3 and DAG
M2- cardiac- Gi protein decreases cAMP leading to increased K+ conductance
M3- smooth muscle of bronchi and vasculature- Gq leads to increased IP3 and DAG
M4- presynaptic autoreceptors controlling Ach release; striatum of basal ganglia for motor control- Gi leads to decreased adenylate cyclase
M5- cerebral vasculature and basal ganglia dopaminergic neurons for motor control- Gq protein leads to increased IP3 and DAG

Question 22

Nicotinic receptor

Answer 22

5 subunits, each coded by different gene
Alpha, beta, gamma, sigma, epsilon
May be heteromeric or homomeric
Fetal- 2 alpha, beta, gamma, sigma
Adult- 2 slpha, beta, gamma, epsilon
Change in subunit decreases the open time of the channel but increases sodium entry

Question 23

Excitatory neurotransmitters in CNS

Answer 23

Glutamate, aspartate, maybe taurine

Question 24

GABA- derivation, removal, metabolism of GABA

Answer 24

Major inhibitory neurotransmitter in brain
Found all over CNS
Derived from glutamate by glutamate decarboxylase (GAD)
Removed from synapse via GAT (GABA transporter)
GAT1- on presynaptic terminal (repackaged into vesicle as is)
GAT2- on glial cells like astrocytes (converted to glutamine then released to be taken back up by presynaptic cell and recycled back into GABA)

Question 25

GABA, Stiff-person and diabetes mellitus diseases

Answer 25

Stiff-person: Increased muscle rigidity and muscle spasms associated with decreasing GABA content Pancreatic beta cells produce and release GABA, so GAD is found in the pancreatic islet. Antibodies to GAD are most common identified type in Type I diabetes

Question 26

GABA(a) receptor

Answer 26

Ionotropic Related to nicotinic Ach receptor 5 subunits alpha, beta, gamma, delta, epsilon Chloride chanel causing influx of chloride - IPSP Benzodiazepine binding site on alpha subunit potentiates increase in chloride conductance Also metabolites of progesterone and deoxycorticosterone potentiate its effects and produce drowsiness

Question 27

GABA(b) receptor

Answer 27

Metabotropic-serpentine Coupled to heterodimer G protein (two of them) Decrease adenylyl cyclase, which leads to an increase in potassium influx and hyperpolarizes Interacts with Gq system leading to DECREASE in IP3/DAG and decrease in calcium influx Produce an IPSP

Question 28

GABA(c) receptor

Answer 28

Found in retina Pentamer of any of 3 different units Ionotropic (also a chloride conductance)

Question 29

Interstitial GABA

Answer 29

There is sufficient interstitial GABA to provide a continual background inhibition in the CNS Mammalian has a lot of GABA receptors that are extrasynaptic and respond to interstitial GABA It is believed that general anesthetics work primarily at these receptors

Question 30

Glycine

Answer 30

Take home message- it does for the spinal cord what we think GABA does for the brain Most prevalent inhibitory NT in the SC Does exist in higher CNS but not as prevalent as GABA Retina, Brainstem, Forebrain Receptor is a pentamer- alpha subunit is site of binding Ionotropic- chloride

Question 31

Purines

Answer 31

Virtually every cell in body expresses some form of a purine receptor PNS- sympathetic/parasympathetic nerves, sensory nerves, intrinsic nerves of gut/heart, motor nerves CNS- Cortex, hippocampus, cerebellum, basal ganglia, midbrain, thalamus, brainstem

Question 32

Strychnine

Answer 32

Blocks glycine receptor

Question 33

Purine neurotransmitters

Answer 33

ATP- receptors largely post synaptic Found in virtually all NT vesicles, so it is considered co-transmitter Adenosine- many receptors are presynaptic (they regulate how much ATP is released). Some are clearly post-synaptic

Question 34

Adenosine production, removal from synaptic cleft

Answer 34

ATP is released in ATPase breaks it down to ADP and then AMP 5-nucleosidase converts AMP into adenosine Adenosine is sometimes considered second messenger since it was not the secreted neurotransmitter Reuptake of adenosine, then adenosine deaminase in the cleft creates inosine, which is removed via circulation

Question 35

Adenosine receptors

Answer 35

P1 receptors Four subtypes A1, A2a, A2b, A3 Metabotropic, either increase or decrease cAMP production

Question 36

ATP receptors

Answer 36

P2X receptros P2X1-7 Ionotropic Cationic ion channels- some allow sodium conductance, some allow calcium, others allow both

Question 37

P2Y receptors

Answer 37

ATP or ADP can open All have greater affinity for ADP Eight different receptors Metabotropic- most lead to Gq G11 activation, some lead to Gi and inhibition of adenylate cyclase

Question 38

Adenosine functions

Answer 38

Sleep induction | Feedback inhibition of ATP release

Question 39

ATP/ADP functions

Answer 39

Major role seems to be related to modifying the action of the "main" neurotransmitter that is in the same vesicle Maintenance of long term potentiation (important for memory) Modification of NT release- GABA, Norepinephrine, Ach, Glutamate and other excitatory AAs

Question 40

Opioid locations

Answer 40

``` Striatum (basal ganglia) Hypothalamus Periaquaductal gray Nucleus parabrachialis (pontine) Raphe nuclei in brainstem ```

Question 41

Opioid precursors

Answer 41

``` All have AA sequence Tyr-Gly-Gly-Phe-X Met-enkephalin Leu-enkephalin Octapeptide (X=Met-Arg-Gly-Leu) Heptapeptide (X=Met-Arg-Phe) ```

Question 42

Pro-opiomelanocortinins (POMC)

Answer 42

Found primarily in pituitary and hypothalamus Beta-endorphins Other endorphins

Question 43

Prodynorphins

Answer 43

``` Localized in hypothalamus, thalamus, brainstem, retina Gives rise to: 3 molecules of leu-enkephalin Dynorphin Alpha-neoendorphin Beta-neoendorphin ```

Question 44

Nociceptin (orphaning FQ)

Answer 44

Has its own opioid receptor, does not bid to others | May participate in opioid induced Hyperalgesia

Question 45

Opioid metabolism

Answer 45

All is enzymatic, likely after uptake Enkephalinase A splits Gly-Phe bond Enkephalinase B splits Gly-Gly bond Aminopeptidase splits Tyr-Gly bond

Question 46

Mu opioid receptor - binding causes what

Answer 46

``` Analgesia Respiratory depression Constipation Euphoria Sedation Increase GH and prolactin secretion Miosis ```

Question 47

Kappa opioid receptor- binding causes what

Answer 47

``` Analgesia Diuresis Sedation Miosis Dysphoria ```

Question 48

Deltoid opioid receptor- binding causes what

Answer 48

Analgesia

Question 49

Commonalities b/w opioid receptors

Answer 49

All are serpentine receptors Gi Inhibit adenylyl cyclase Indirectly alter other ion flows Mu- increase K+ efflux and lead to hyperpolarization Kappa/Delta- produce decrease in calcium influx

Question 50

Endogenous endocannabinoid ligands

Answer 50

Anandamide (AEA)-degraded by fatty acid amide hydrolase (FAAH). Polymorphisms in this gene will cause reduced nociception, especially to heat 2-Arachidonylglycerol- degraded by mono-acyl glycerol lipase Both can be metabolized via cyclooxygenase and ipoxygenase pathways *important- these pathways feed into prostaglandin synthesis

Question 51

CB1 general info

Answer 51

Most abundant G protein receptor in the brain Utilizes Gi- reduces adenylyl cyclase Located on presynaptic terminals in CNS and PNS, mainly on EAA or GABA releasing neurons Binds anandamide and 2AG equally well Decreases NT release, effects are difficult to predict because it interacts with both EAA and GABA as well

Question 52

Spinal cord CB1

Answer 52

Associated with modification of nociceptive inputs

Question 53

Neocortical CB1

Answer 53

Associated with neuroprotection against excitotoxicity

Question 54

Hippocampal CB1

Answer 54

Associated with changes in affect

Question 55

CB2

Answer 55

Binds 2-AG better than anandamide Located on microglia Can be found on neurons in response to neuronal injury, brain inflammation responses Modify cytokine release, can be anti-inflammatory Found on GI tissue, linked to IBD treatment

Question 56

Endocannabinoids are derived from

Answer 56

Membrane lipids- arachidonic acid | Occurs in presynaptic terminal

Question 57

EAAs

Answer 57

Aspartate and Glutamate

Question 58

NMDA receptor

Answer 58

Activated by EAAs Ionotropic- allows calcium influx NO is a byproduct of activating NMDA receptor Glycine binding site- glycine must be present with EAA to activate channel Magnesium binding site- Mg sits in channel and prevents Ca2+ influx when membrane is at resting potential (makes channel both voltage and ligand gated) PCP binding site- PCP blocks the channel

Question 59

Non-NMDA receptors

Answer 59

``` Ionotropic- primarily Na influx AMPA- Activated by EAAs AMPA has a Benzodiazepine binding site- reduces sodium influx when channel opens Kainate- Activated by EAAs -sodium and calcium influx ```

Question 60

EPSP of EAA receptors

Answer 60

Activation of Non-NMDA receptors produces normal EPSP | NMDA receptor produces a long and slow EPSP because of the magnesium receptors blocking the channel at rest

Question 61

Functions of Non-NMDA receptors

Answer 61

Primary sensory afferents | Upper motor neurons

Question 62

Functions of NMDA receptors

Answer 62

Critical in short and long term memory formation | Synaptic plasticity in many forms

Question 63

Getting rid of EAAs

Answer 63

EAAs are taken into glial cells after used and then converted glutamine and then released to be taken back up by pre-synaptic neuron to reform glutamate

Question 64

NO effects on neurons

Answer 64

Long-term potentiation In hippocampus & cerebellum Cardiovascular and respiratory controls in pons/medulla In high concentrations it is toxic to neurons and will kill the neighbors of the neuron that made it

Question 65

Non-neural functions of NO

Answer 65

Relaxation of smooth muscle and vasodilation