Neurotransmitters, Chemical Messengers, And Excitotoxicity Flashcards
Neurotransmitters are classified into what two categories?5
Small molecules: rapidly acting
Neuropeptides: slowly acting (need to bind to receptor); growth factors, receptor modulation, synaptic maturation
What are the two categories of neurotransmitter receptors?
Ionotropic: increase conductance to certain ions by binding to ligand-activated channels; binding induces rapid conformational change -> increases the diameter of the pore -> allow ion influx; faster
Metabotropic: act to alter membrane properties via a second messenger; G-protein coupled receptors; slower
How are neurotransmitter receptors classified?
GPCR: G-protein coupled receptor
RTK: receptor tyrosine kinase; activates tyrosine kinase activity in the cell; growth factor receptors
LGIC: ligand-gated ion channels; ionotropic
NTFR: nuclear transcription factor receptors; steroid receptors
How are neurotransmitters inactivated or terminated?
Re-uptake into the presynaptic neuron by specific transporters
Accumulation in glial cells
Enzymatic degradation (ACh)
Diffusion away from synapse
What is the fx of a synaptic transmitter after it is released?
What are the steps a neurotransmitter takes to have an effect?
Stimulate, inhibit, or modulate the postsynaptic neuron
AP opens Ca channels in the presynaptic neuron -> stimulates vesicle fusion to active zones -> vesicles release content into the synaptic cleft -> neurotransmitters induce receptor activation on the postsynaptic membrane -> depolarize the postsynaptic neuron
What neurotransmitters are classified as biogenic amines/monoamines?
Catecholamines: epinephrine, norepinephrine, dopamine
Histamine
Serotonin
Catecholamines are derived from _____.
What is the rate limiting step?
What is the sequence to get from tyrosine to epinephrine?
What converts norepinephrine to epinephrine?
Tyrosine
Tyrosine -> L-DOPA by tyrosine hydroxylase
Tyrosine -> L-DOPA -> dopamine -> norepinephrine -> epinephrine
Phenylethanolamine N-methyltransferase (PNMT)
Dopamine is stored in vesicles in neurons; _____ are important in allowing the release of monoamines from vesicles into the synaptic cleft.
Vesicular monoamine transporters (VMAT)
How are monoamines terminated?
COMT: mechanism for inactivation of epi released by the adrenal medulla and CNS
MAO: has two isoforms and is a target for neuropsychiatric disorders
Where is norepinephrine located?
What is its fx?
What releases epinephrine?
Locus coeruleus
Waking up and awareness
Adrenal medulla
Dopamine has neurons located in the ____ and the ____ of the midbrain; these project to the prefrontal cortex and parts of the limbic system.
Substantia nigra (project to the striatum); ventral tegmental area
What four major systems use dopamine?
Substantia nigra: motor; damaged in Parkinson’s
Mesolimbic: VTA to nucleus accumbens; central to pleasure, reward, and addiction
Mesocortical: VTA to frontal cortex; attention, high level of consciousness
Tuberinfundibular: hypothalamus to anterior pituitary; suppresses the release of prolactin
*VTA = ventral tegmental area
Histamine is found in the ____ of the posterior hypothalamus and projects throughout the brain.
Fx?
What are the two receptors?
What degrades histamine?
Tubomammillary nucleus (TMN)
Wakefulness
H1 and H2
Diamine oxidase
Serotonin is located in the ____ and projects to many areas of the CNS.
Fx?
Derived from ____.
What is the rate limiting step?
5HTP -> serotonin uses what enzyme?
What metabolizes serotonin?
Raphe nuclei
Controls attention and mood, involved in depression
Tryptophan
Tryptophan -> 5HTP using tryptophan hydroxylase
5-HT decarboxylase
MAO
What are serotonin receptors and what is their fx?
5-HT2a: smooth m contraction
5-HT3: vomiting (ionotropic)
5-HT6: high affinity for several antidepressant
5-HT2c: role in controlling normal body weight and preventing seizures
Where are cholinergic neurotransmitters located?
Pons, midbrain, motor cortex, autonomic, NMJ
Ach has neurons located in the ____, which includes ____. The neurons project to _____.
Other Ach neurons originate in ____ and project to the dorsal thalamus and forebrain.
Fx?
Basal forebrain complex; septal nuclei and nucleus basalis; hippocampus and neocortex
Pontomesencephalotegmental cholinergic complex
Learning and memory
What are the fx of Ach?
Where is it stored?
What moves it from cytosol into vesicles?
What inhibits Ach?
Producing consciousness but not awareness; voluntary motion; initiates REM sleep; excitatory
Stored in clear vesicles
Vesicular Ach transport protein (VAchT)
Acetylcholinesterase bound to post synaptic cell membranes
What are two Ach receptors?
Nicotine receptors: ionotropic; allow for Na entrance and some allow Ca influx
Muscarinic receptors: metabotropic; 2nd messenger signaling systems
What are the five types of Ach muscarinic receptors?
What are the Ach nicotinic receptors?
M1: neuronal; induce signaling of IP3/DAG and increases Ca
M3: smooth muscle; G-coupled
M5: G-coupled
M2: cardiac; inhibitory; decrease cAMP, stop Ca influx, increase K effluent and hyperpolarize the cell
M4: inhibitory
Located at NMJ, autonomic ganglia; has 5 subunits (alpha, beta, gamma, delta, epsilon)
What are the excitatory AA neurotransmitters?
Inhibitory?
Glutamate, aspartame
GABA, glycine
What is the location of GABA?
Fx?
Synthesis?
Termination/transmission?
Cortex, cerebellum
Inhibitory; released by interneurons; producing consciousness/awareness and controls voluntary motion
Synthesized from glutamate by glutamate decarboxylase and feeds into the Krebs cycle
Catabolized by GABA-transaminase to SSA
What are the three GABA receptors?
GABAa: conducts Cl (ionotropic) -> depresses excitability -> inhibitory; benzodiazepine receptor; binding sites for barbiturates; ethanol augments GABA mediated Cl influx (sedative)
GABAb: metabotropic; mediates inhibitory NT release; increases K/decreases Ca to hyperpolarize the cell
GABAc
What is the location of glycine?
Fx?
What is the effect of strychnine on glycine?
Spinal cord
Inhibitory NT
Loss of inhibitory regulation leads to death by respiratory failure following convulsions
Opioids are ____ that influence neuronal activity.
Examples and what are they derived from?
Neuropeptides
Endorphins: POMC
Enkephalins: pro-enkephalins
Dynorphins: pro-dynorphin
How do opioid receptors fx?
What are the four receptors that bind to opioids and how do they work?
Inhibitory (Gi) and inhibit adenylyl cyclase and indirectly alters ion flow
Mu: analgesia; respiration depression, constipation, euphoria, sedation, increases GH and prolactin and miosis; increases K efflux (hyperpolarization)
Kappa: analgesia; diuresis, sedation, miosis, dysphoria; decreases Ca influx (hyperpolarization)
Delta: analgesia; decreases Ca influx
Nociceptin: hyperalgesia; produces anxiety, depression, and tolerance to Mu opioid agonists
What are the ligands of endocannabinoids?
Why are they atypical?
Anandamide, 2-arachidonylglycerol (2-AG) = lipid molecules
Not stored in vesicles, not released from pre-synaptic terminals, are released from post-synaptic locus and have retrograde actions
How does the CB1 receptor for endocannabinoids fx?
What does SC CB1 affect?
What does neocortical CB1?
What does hippocampus and basal ganglia CB1 affect?
Uses Gi signaling to reduces adenylyl cyclase activity
Localized on axons and pre-synaptic terminals to decreases NT release
**Interacts with EAA and GABA, inhibiting them in the pre-synaptic terminal
SC SB1 receptors are associated with modulation of nociception
Neocortical CB1 receptors are associated with protecting against excitotoxicity
Hippocampus and basal ganglia CB1 receptors are associated with changes in affect and motor effects
How do CB2 receptors for endocannabinoids fx in the brain, immune system, and viscera?
Brain: found on microglia; target of interest in Alzheimer’s
Immune system: lymphocytes, thymus, spleen, tonsils; modifies cytokine release; ant-inflammatory
Viscera: wide-spread in gut and other viscera; CB2 agonists used to treat inflammatory bowl disease and prevent inflammatory cystitis in bladder pain syndromes
Glutamate is derived from ___.
Aspartate is derived from ____ and located in ____.
They are classified as ____.
Alpha-ketoglutarate
Oxaloacetate; visual cortex and pyramidal cells
Excitatory amino acids (EAA)
What are the two types of glutamate receptors?
Metabotropic: modulates synaptic signaling of receptors and transmitter release; located on pre and post synaptic locations
Ionotropic: NMDA and non-NMDA receptors (kainate and AMPA)
Glutamate AMPA receptors are ___ and NMDA is ____.
NMDA receptor is blocked by ____ on the postsynaptic terminal. How is this blockage removed?
Fast conducting/depolarization, voltage independent, little impact on Ca
Slow conducting, determines the duration of depolarization, voltage dependent, strong influence on Ca
Mg; AMPA receptor receives the NT, allows the influx of Na, and depolarizes the cell -> once the cell is depolarizes to >60mV, the Mg is displaced, opening the NMDA receptor -> NMDA receptor bound to glycine allows the influx of Ca, further depolarizing the cell, and generating an AP
Describe the excitatory glutamate synapse.
Glutamine inside cell -> glutamate by glutaminase -> glutamate is packaged into vesicles inside the cell -> released into the synaptic cleft -> binds to receptors (AMPA, NMDA, kainate, metabotropic GPCR) on the postsynaptic membrane -> ions flow into the cell and depolarizes the cell -> glutamate reuptake back into the cell -> catabolized by glutamine synthase back into glutamine
What happens if there is excess glutamate being produced during the excitatory glutamate synapse?
Too much glutamate prevents it from being inactivated and reuptake back into the cell -> floods the synaptic cleft -> activates extra synaptic glutamate receptors -> excitotoxicity and cell death
What activates the glutamate receptor NMDA?
Fx?
What are its other binding sites?
N-methyl-D-aspartate, glutamate, aspartate
Allows Ca influx to depolarizes the cell; slow onset
Glutamate: EPSP
Glycine: co-agonist; has to be present for EAA to work but can’t open the channel
Mg: blocks the channel; depolarization kicks out Mg to open channel
PCP: blocks the channel
Non-NMDA allow for ____.
What are its two types?
Activation of these leads to ____.
What are AMPA binding sites?
Na influx
AMPA, kainate
Excitatory post-synaptic potential (EPSP)
Glutamate, benzodiazepine (inhibit NT)
What are the fx of the EAA receptors in the CNS?
Non-NMDA: primary afferents, premotor (UMN)
NMDA: long-term changes in synaptic strength, learning, memory
Metabotropic: learning, memory, motor system
What are uptake systems for getting rid of EAA?
Adjacent neurons and glia: Na dependent secondary to active transport; have a high affinity
Glia: converts glutamate -> glutamine and release it into the ECF; neurons take the glutamine and covert it back to glutamate
Nitric oxide acts as a ____ in the CNS.
What are the characteristics of NO?
Gasotransmitter
Independent of intracellular Ca release, release upon nerve stimulation, diffuses through membrane, acts on pre and post synaptic membranes, can be a retrograde messenger, not found in synaptic vesicles, not release from nerve terminals, not stored
When Mg is removed from NMDA, there is an influx of Ca. The Ca binds with ____ and activates ____.
NOS catalyze the reaction that converts arginine to _____.
Calcineurin; NOS (nitric oxide synthase)
NO
What are the fx of NO?
What is the negative effect of NO?
Relaxes smooth m, involved in memory, enhances NT release in the CNS, cardio and respiratory control
Leads to the production of free radicals
____ is the mechanism to explain why there is continual neuron death after an ischemic event.
It is based on the idea that overstimulation of the ____ can cause cell death even in neurons not directly involved in the ischemic event.
Examples?
What area is most affected?
Excitotoxicity
EAA system
Cerebral ischemia/stoke, hypoxia, anoxia, mechanical trauma to CNS, hypoglycemia, epilepsy
Anoxic core (area of the ischemic event) -> leads to O2 deprivation, cells unable to meet metabolic needs, depolarization of membrane
What happens within mixtures of the event initiating excitotoxic pathways?
Neurons get depolarized and flood the synaptic cleft with glutamate -> post synaptic cell is activated but can only handle so much -> ATP levels fall to 0 inside the neurons -> Na/K ATPase ceases to fx -> cell depolarizes -> AP and release of more NT including EAA -> less Na in synaptic cleft therefore no AMPA so no reuptake of EAA -> less Ca in synaptic cleft so no NMDA activation -> soooo much glutamate
Excess glutamate can stimulate receptors outside of the post-synaptic membrane. These stimulate the axon and allow for ___ flooding into the cytosol of the cell.
What does this cause?
Ca
Activation of phospholipase A2
Activation of calcineurin (phosphatase)
Activation of Mu-calpain (protease)
Activation of apoptotic pathway
Excess Ca causing the activation of phospholipase A2 cause the release of ____ from the membrane and damages the cell membrane.
Arachidonate binds to the _____ on the ER. Causes the release of more ____ from intracellular stores.
Increase Ca activates a kinase that phosphorylates _____ causing ____. Also impairs ____.
Arachidonate
Ryanodine receptor
Ca
eIF2alpha: fx in transcription/translation of protein; when phosphorylated it stops making protein
Impairs mitochondria fx
Excess Ca causes activation of Mu-calpain (protease). What is its fx?
Cleaves spectrin and eIF4G which are involved in protein synthesis and maintaining structure of cell membrane -> cleavage causes lack of protein formation and cell damage
Excess Ca causes the activation of calcineurin. What is the fx?
Activates phosphatase -> activates NOS -> increases NO synthesis -> cause vasodilation and contributes to edema
As mitochondrial membranes are disrupted from the high Ca influx, ____ are activated.
Examples?
Excitotoxicity will also suppress ____ that will normally inhibit cytochrome C and caspase 9.
Apoptotic pathways
Cytochrome C, caspase 9 -> caspase 3 -> proteolytic enzyme -> apoptosis
Bcl2 enzymes
In an ischemic event, with a pt in a hypoxia state, what happens if the pt is flooded with O2 too fast?
This will cause a reperfusion injury: neurons can no longer process the O2 -> O2 will end up as a free radical
Normally mitochondria will take the O2 and generate ATP
