Chemical Messengers and Excitotoxicity Flashcards
What are the 3 things that are vital to our normal function?
EAA neurotransmitter system, calcium, and oxygen
When does over-stimulation of the EAA system occur?
After ischemia in the brain; responsible for damage to neurons whether or not they were exposed to the ischemia
What are some things that over-stimulation of the EAA system is implicated in?
Strokes, global hypoxia/anoxia, traumatic injury to the brain, hypoglycemia, and epilepsy
What is step 1 in excitotoxicity?
Depolarization of the membrane
Describe step 1 in excitotoxicity?
Starts with a localized event (stroke)
1) Immediate loss of blood flow
2) Within 4 minutes, O2 levels drop to 0 near mitochondria and ATP production ceases
3) Na/K ATPase activity drops quickly
4) Causes depolarization of neuronal cell membrane
What is step 2 in excitotoxicity?
Action potentials
Describe step 2 in excitotoxicity?
As neurons depolarize, they reach threshold and the voltage-gated sodium channels open, leading to action potentials
What is step 3 in excitotoxicity?
Releasing the EAA
Describe step 3 in excitotoxicity?
Once action potentials reach presynaptic terminal, release of the neurotransmitter into the cleft occurs; because so many synapses in the cortex use EAA, this results in a lot of EAA being released into many different parts of the brain
What is the uptake of EAA dependent on?
Secondary active transport of Na
What is step 4 in excitotoxicity?
Increasing calcium levels in the post-synaptic cell
Describe step 4 in excitotoxicity?
Many synapses express both non-NMDA and NMDA receptors; activation of the non-NMDA produces the depolarization that will force the Mg out of the Ca channel, allowing Ca to enter the post-synaptic cell
What are the consequences of high intracellular calcium? What does this cause?
1) Increase in phospholipase A activity
2) Activation of u(mu)-calpain
3) Activation of calcineurin
4) Activation of the apoptotic pathway
Describe what happens when there is an increase in phospholipase A activity
Acts on membrane to release arachidonic acid and causes physical damage to the membrane; arachidonic acid release leads to Ca release from ER and mito, unfolded protein response (ER stops making proteins), eIF2a-kinase activation, and mitochondrial dysfunction
Describe what happens when u(mu)-calpain is activated
Proteolysis of structural proteins including spectrin, proteolysis of other enzymes and proteins including eIF4G; leads to metabolic and structural impairment of neurons
Describe what happens when calcineurin is activated
Leads to excess production of nitric oxide (NO) via activation of nitric oxide synthase (NOS)
Describe what happens when the apoptotic pathway is activated
Results as a consequence of the previous steps, particularly the release of Ca from intracellular stores; mitochondria release enzymes including caspase 9; caspase 9 release leads to activation of caspase 3, which is pro-apoptotic
Repurfusion (bringing back oxygen) sounds like a good idea after this has taken place, however the mitochondria have released many of their enzymes, impairing their ability to use oxygen to make ATP. So, what happens to the oxygen that is brought in?
Results in production of free radicals; some mitochondria may be able to synthesize ATP but a different set of proteins are now active compared to the healthy state
The ATP that is able to be produced in this unhealthy state, what happens to it?
Kinases take ATP -> ADP + PO4
Leads to phosphorylation which further modifies enzyme action; phosphorylation of eIF2a kinase leads to a further decrease in protein synthesis and further activates caspase 3, which further increases apoptotic signaling
What is an ionotropic receptor?
Receptor is associated with an ion channel that opens in response to the binding of the neurotransmitter
Also called ligand-gated ion channel
What is a metabotropic (serpentine) receptor?
Binding of neurotransmitter to the receptor activates a 2nd messenger system
What are the 2nd messenger systems and what do they do?
Gs: stimulates adenylate cyclase
Gi: inhibits adenylate cyclase
Gq: production of DAG and IP3 (think calcium release from intracellular stores)
What are EPSPs and IPSPs?
EPSP: excitatory post-synaptic potential; depolarizes cell membrane
IPSP: inhibitory post-synaptic potential; hyperpolarizes cell membrane
What neurotransmitters are part of the monoamines group?
Epinephrine, norepinephrine, dopamine, serotonin, histamine
Where do you find norepinephrine? Epinephrine?
Norepi: locus ceruleus, pontine/medullary areas, wakefulness/alertness
Epi: medulla
Where are epinephrine, dopamine, and norepinephrine derived from?
Tyrosine
What moves norepi and epi into the vesicles? What inhibits this process?
Moved into vesicles by VMAT1 and VMAT2; inhibited by reserpine, which leads to synaptic failure
What receptors do epi and norepi bind to?
alpha and beta adrenergic
Where do you find dopamine?
Basal ganglia, hypothalamus, limbic system, and cortex
What breaks down dopamine and serotonin?
MAO and COMT
Where do you find serotonin?
Hypothalamic and limbic systems, cerebellum, brainstem, and raphe nuclei
Where is serotonin derived from?
Tryptophan
Where is histamine found?
Tuberomammillary nucleus of hypothalamus
Where is histamine derived from?
Histidine
What breaks down histamine?
Diamine oxidase and COMT
Where is acetylcholine found?
Striatum of basal ganglia, midbrain, and pons
What is acetylcholine synthesized from?
Choline and acetate
What receptors do acetylcholine bind to?
Muscarinic and nicotinic
What are the inhibitory amino acids?
GABA and glycine
What is GABA critical in?
Consciousness, motor control, and vision (retina)
What is GABA synthesized from?
Glutamate
What removes GABA and glycine from the synapse?
GAT proteins
Where is glycine found?
Spinal cord and medulla
Where are the purines (ATP, ADP, adensoine) found?
Virtually everywhere, but special mention to cortex, cerebellum, hippocampus, and basal ganglia
What are considered opioids?
Endorphins, enkephalins, dynorphins, and nociceptin
What is the function of the opioids?
Modification of nociceptive inputs and mood
What are endorphins derived from?
Proopiomelanocortinin (POMC)
What are enkephalins derived from?
Pro-enkephalin
What are dynorphins derived from?
Pro-dynorphin
What is nociceptin derived from?
Orphanin FQ
What breaks down opioids?
Enkephalinase and aminopeptidiase
What are the endocannabinoids?
Anandamide and 2-arachidonylglycerol (2AG)
Where are the endocannabinoids found?
Basal ganglia, spinal cord, cortex, hippocampus, and hypothalamus
What is anandamide derived from?
N-arachidonoyl phosphatidyl ethanol
What is 2-arachidonylglycerol derived from?
Arachidonoyl-containing phosphatidyl inositol bis-phosphate
What are the excitatory amino acids?
Glutamate and aspartate
What receptors do EAA bind to?
NMDA and non-NMDA receptors
What are the modulatroy sites on the NMDA receptors?
Glycine, PCP, and Mg2+ binding sites
What are the non-NMDA receptor types?
AMPA and kainate
What do NMDA and non-NMDA receptors function in?
NMDA: short and long-term memory
non-NMDA: primary sensory afferents and UMNs
What are the neural functions of nitric oxide?
Long-term potentiation of memory in hippocampus and cerebellum; also cariovascular and respiratory control in pons and medulla
What are the non-neural functions of nitric oxide?
Immunological and cardiovascular functions
What are the cons of nitric oxide?
Very unstable, leads to production of free radicals, and it is toxic to neurons in high concentrations
