Week 1 - CNS Neurotransmitters Flashcards
compared to other signaling molecules, what distance do neurotransmitters act over?
tiny distance
two major types of neurotransmitters and examples
- small molecules (classical neurotransmitters)
- ACh
- AA (glutamate, GABA, gly)
- biogenic amines (dopamine, norepinephrine, serotonin) - neuropeptides (nonclassical neurotransmitters)
- more than 100+ different peptides (brain-gut, opiods)
- typically 3-36 AA long
how is the concentration of nt in synaptic cleft regulated?
tightly regulated via:
- nt synthesis
- packaging
- release
- removal (terminates synaptic transmission)
small molecule transmitter transport
slow axonal transport, but signal quickly
- synthesized w/in presynaptic terminal and packaged into vesicles by specific transport PRO in vesicle membrane
- can respond to increased demand rapidly b/c they are synthesized in nerve terminal
neuropeptide transmitter transport
fast axonal transport, but signal slowly
- synthesized and packaged into transport vesicles w/in cell body, then transported to nerve terminal via fast axonal transport
- cannot respond quickly to increased demand b/c synthesized in cell body and must be transported the entire length of the axon to the release site
- release must be carefully regulated to prevent depletion
2 types of neurotransmitter receptors
- ionotropic (fast ligand-gated ion channels)
2. metabotropic (slow GPCR that signal to channel)
ionotropic nt receptors
ligand-gated ion channels that open in direct response to ligand binding
- consist of 4-5 subunits that contain 3-4 transmembrane domains
- usually multiple subunits that can be assembled to generate diverse set of receptors
- -there are rules that govern which set of subunits are found w/in each receptor
- -for most receptors, depending on composition of subunits, each receptor subtype will have distinct properties, meaning some drugs may work on one patient but not another
metabotropic nt receptors
GPCR that activate G-PRO in response to ligand binding
- activated G-PRO modulate ion channels directly or indirectly through intracellular enzymes and second messengers
- monomeric PRO containing 7 transmembrane domains
- wide variety for most nt, which all have different properties
ACh in peripheral nervous system
in neuromuscular junction
- synapses in ganglia of visceral motor system
- slows the heart
ACh in central nervous system
- interneurons in brainstem and forebrain
- large neurons in basal forebrain that project to cerebral cortex
- function in CNS not well understood, but believe it’s in attention, arousal, and reward plasticity
- -enhances sensory functions upon waking
- damage to cholinergic system is associated with memory deficits in AD
ACh synthesis, packaging, and removal
- synthesized enzymatically in nerve terminal from ACoA and choline
- packaged into synaptic vessels by vesicular ACh transporter
- removed from synaptic cleft via cleavage to acetate and choline by acetylcholinesterase
- choline is taken up by nerve terminal via specific transporter and is used to synthesize more ACh
why are organophosphates and nerve gas lethal?
they inhibit acetylcholinesterase and cause ACh to accumulate at cholinergic synapses
- causes continued depolarization of postsynaptic cell, making it refractory to subsequent ACh release
- at NMJ, this causes muscle paralysis
what kines of receptors do ACh have?
both ionotropic (nicotinic) and metabotropic (muscarinic)
ionotropic ACh receptors
- what do they do?
- where are they?
- composition?
excitatory cation-selective channels
- mediate synaptic transmission at NMJ
- also present in CNS
- muscle and neuronal receptors have different subunit compositions, but both consist of 5 subunits total
metaboctropic ACh receptors
- what do they do?
- where are they?
- what are antagonists and how are they used?
mediate most ACh effects in brain
- highly expressed in forebrain
- also present in peripheral panglia where they mediate responses of autonomic effector organs (heart, smooth muscle, etc.)
- antagonists atropine (pupil dilation) and scopolamine (motion sickness) are therapeutically useful
myasthenia gravis epidemiology and symptoms
14: 100,000 people; onset in 20-30s women or 70-80s men
- muscle fatigability that worsens later in the day or after repetitive exercise, but improves with rest
- diplopia, ptosis
- difficulty speaking, swallowing, chewing
- weakness in arms and legs
what is myasthenia gravis caused by?
autoimmune disease due to antibodies against muscle nicotinic ACh receptors causing increased turnover of receptors
- altered structure at NMJ causes:
- -decreased concentration of receptors in postsynaptic membrane
- sparse and shallow junctional folds
- expanded synaptic cleft
what does myasthenia gravis do to neuromuscular transmission?
reduced efficiency of neuromuscular transmission
- size of miniature endplate potentials (MEPPs) is reduced
- size of endplate potentials (EPPs) is reduced
- probability that a presynaptic AP will elicit a postsynaptic muscle action is reduced
- during repeated stimulation, compound AP in muscle decreases in size (fatigues)
myasthenia gravis treatment
- cholinesterase inhibitors (ACh stays in synaptic cleft longer, so more changes to bind and activate receptors)
- thymectomy (recommended for most patients, may take years to see max results)
- corticosteroids (respond well, but major side effects)
- immunosuppressants (decreased autoimmune response to receptors)
glutamate in normal brain function
most prominent and common transmitter used by nearly all excitatory neurons in brain
-more than half of all brain synapses use glutamate
excitotoxicity of glutamate
- high extracellular concentrations of glutamate are toxic to neurons
- excessive activation of glutamate receptors can excite neuron to death
- thought to cause neuronal damage during strokes; oxygen deprivation slows glutamate reuptake
- considerable interest in using glutamate receptor antagonists to block excitotoxic nerve damage following stroke
- also involved in other acute forms of neuronal insult, like hypoglycemia, trauma, and repeated intense seizures
synthesis, packaging, and removal of glutamate
can’t cross BBB, but glutamine can
- synthesized in nerve terminal from glutamine (by glutaminase), or transamination of alpha-ketoglutarate
- packaged into synaptic vesicles by vesicular glutamate transporter (VGLUT)
- removed from synaptic cleft by high affinity glutamate transporters on both nerve terminal and nearby glial cells
- in glial cells, glutamate is converted to glutamine (via glutamine synthetase) and transported out of the cell and back into nerve terminals
what kinds of glutamate receptors are there?
both ionotropic (NMDA, AMPA, kainate) and metabotropic (3 classes)
ionotropic glutamate receptors
excitatory cation-selective (Na+) channels
- NMDA, AMPA, and kainate
- NMDA receptors have unique properties
- -Ca++ can pass thru
- -ion flow is voltage-dependent b/c of Mg++ binding
- glycine binding is required to open channel
metabotropic glutamate receptors
three classes, and activation can increase or decrease excitability of postsynaptic cell
what are the major inhibitory neurotransmitters in the CNS?
GABA and Glycine
- GABA is widely distributed to brain; 1/3 of brain synapses use GABA, along with local interneurons and Purkinje fibers of cerebellum
- glycine is predominantly used at synapses in spinal cord