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
GABA synthesis, packaging, and removal, and what decreased GABA function does
made in nerve terminals from glutamate via glutamic acid decarboxylase + pyridoxal phosphate (PLP; from B6)
- packaged in synaptic vesicles by vesicular inhibitory AA transporter (VIATT)
- removed from synaptic cleft by specific transporters on nerve terminals and nearby glia
- decreased GABA function can cause epilepsy
what does GABA-T do?
turns GABA into glutamate then glutamine to go into glutamate cycle
glycine synthesis, packaging, and removal, and what defects in glycine transporters cause
synthesized in nerve terminals from serine
- packaged into synaptic vesicles by vesicular inhibitory AA transport (VIATT; just like GABA)
- removed from synaptic cleft by specific transporters on nerve terminals and nearby glia
- excess synaptic glycine caused by defects in glycine transporter causes neonatal diseases characterized by lethargy and mental retardation
what kinds of receptors are GABA and glycine?
GABA-A, GABA-C, and glycine are ionotropic inhibitory chloride channels
GABA-B is only metabotropic channel
ionotropic GABA receptors and effects of agonists
GABA-A/C; inhibitory chloride channels
- GABA receptor agonists enhance GABA-ergic transmission
- -benzodazepines (Valium) used as tranquilizers
- -barbiturates (phenobarbital) used as anesthetics to control epilepsy
ionotropic glycine receptors and effects of antagonists
inhibitory chloride channels
- glycine receptor antagonists like strychnine block receptors
- -cause overreactivity of spinal cord and brainstem, leading to seizures
- -used to poison rodents
metabotropic GABA receptors
GABA-B only; widely distributed in brain
-activation produces inhibitory postsynaptic response
how are glutamate and GABA receptors expressed in brain compared to biogenic amines?
glutamate and GABA are very widely made
-data shows that glutamate are made and utilized ubiquitously across brain
biogenic amines are limited and specific expression of genes, but broadly expressed receptors (80-90% of dopamine innervation goes to striatum)
biogenic amines as neurotransmitters
aminergic neurons project widely in brain and help modulate intensity of more specific neuronal signals
- used by relatively few neurons in brain, but very important to maintenance of mental health
- -implicated in a wide range of behaviors
- -defects in functions implicated in most psychiatric disorders
biogenic amines synthesis, packaging, and removal
synthesized in nerve terminals
- packaged in vesicular monoamine transporter (VMAT)
- removal into nerve terminals (back into same bouton)
relationship between biogenic amines and catecholamines
catecholamines are dopamine, epinephrine, norepinephrine
biogenic amines are previous 3 + histamine and serotonin
biogenic amine receptors
metabotropic, but serotonin also has ionotropic
synthesis of catecholamines
- tyrosine –> DOPA (via tyrosine hydroxylase)
- DOPA –> dopamine (via DOPA decarboxylase)
- dopamine –> norepinephrine (via dopamine hydroxylase)
- norepinephrine –> epinephrine (via phenylethanol-amine N-methyl transferase)
serotonin synthesis
- tryptophan –> 5-hydroxytryptophan (via tryptophan-5-hydroxylase)
- 5-hydroxytryptophan –> serotonin (via aromatic L-amino acid decarboxylase)
distribution of dopamine containing neurons and their projections and function in substantia nigra
major; 80% of brain dopamine found in corpus striatum (caudate and putamen), which receives major input from substantia nigra
-function to coordinate body movements
what happens to dopamine in Parkinson’s disease? how does treatment work?
substantia nigra neurons degenerate, leading to motor dysfunction b/c dopamine input to striatum decreases
- L-DOPA (precursor) will cross BBB, which increases dopamine levels in the striatum
- -cells continue to die, though, so only temporary
distribution of dopamine containing neurons and their projections and function in midbrain
major; project from ventral tegmental area to ventral parts of striatum
- involved in motivation, reward, and reinforcement
- addictive drugs raise dopamine levels by interfering with reuptake by dopamine transporters
distribution of dopamine containing neurons and their projections and function in cortex
minor; involved in emotional behavior
distribution of norepinephrine containing neurons and their projections and function in locus coeruleus
goes to a variety of forebrain and brainstem targets
- influence sleep and wakefulness, attention, and feeding behavior
- for PNS, is prominent in sympathetic ganglion cells as major transmitter of sympathetic motor system
dopamine receptors
metatropic only
- act by activating or inhibiting adenylyl cyclase
- antagonists of receptors in medulla used as anti-emetics to treat nausea and vomiting
norepinephrine receptors
metatropic only
- alpha/beta adrenergic receptors (also used by epinephrine)
- agonists and antagonists used therapeutically for many conditions
- -cardiac arrhythmias and migraine headaches
- -most of these effects are mediated by receptors in smooth muscle, not brain
catecholamine removal from synaptic cleft and effects of cocaine and amphetamine
reuptake into nerve terminals and glia
- mediated by transmitter-specific plasma membrane transporters
- -cocaine inhibits dopamine transporter, causing net increase in release of dopamine
- -amphetamine inhibits both dopamine and norepinephrine transporters, causing net increase in release of transmitters
distribution of serotonin containing neurons and their projections in raphe nuclei
in upper brainstem; project widely to forebrain and also to brainstem
-implicated in regulation of sleep, eating, arousal, and wakefulness
what do drugs to treat depression and anxiety act on?
serotonergic neurons
what is another name for serotonin?
5-hydroxytryptamine (5-HT)
serotonin reuptake
reuptake into nerve terminal by specific serotonin transporter (SERT)
what are serotonin receptors?
both metabotropic (majority) and ionotropic (minority)
metabotropic serotonin receptors
implicated in emotions, circadian rhythms, motor behaviors, and mental arousal
- impairment implicated in many psychiatric disorders
- activation mediates satiety and decreased food consumption
ionotropic serotonin receptors
non-selective excitatory cation channel
-targets for many drugs including some used to prevent nausea
why is it hard to disentangle biogenic amine functions from each other?
they all impinge on each other
how to anti-psychotic drugs work?
block dopamine receptors, suggesting excess dopamine release may cause some psychotic illnesses like schizophrenia
how do anti-anxiety drugs work?
MAO inhibitors block breakdown of biogenic amines
-inhibitors of serotonin receptors
what are the 3 classes of anti-depressants and how do they work?
- MAO inhibitors block breakdown of biogenic amines
- tricyclic anti-depressants block reuptake of NE and 5HT
- serotonin reuptake inhibitors (Prozac) act specifically on serotonin transporters
peptide neurotransmitters overview
implicated in modulating emotions, perception of pain, and responses to stress
-biological activity is dependent on their AA sequence
5 categories of peptide neurotransmitters
- brain-gut peptides
- opioid peptides
- pituitary peptides
- hypothalamic-releasing peptides
- miscellaneous peptides
synthesis and processing of neuropeptides
- synthesized as pre-propeptides in ER in neuronal cell body
- processed into pro-peptides in ER by removal of ER targeting signal
- final processing to individual active peptides occurs in vesicles after they bud from trans Golgi
- individual pro-peptides can give rise to multiple active peptides w/in a single vesicle
peptide neurotransmitter release and removal
often co-released with small-molecule neurotransmitters
- removed from synaptic cleft via degradation by peptidases
- some peptides are degraded to more active peptides within synaptic cleft by endopeptidases
peptide neurotransmitter receptors
use metabotropic receptors
- activated at relatively low peptide concentrations
- little is known about receptors
opioid peptides
widely distributed throughout brain
-tend to be depressants, and can act as analgesics (during acupuncture)
morphine
opioid peptide isolated from poppies
- one of the most effective analgesics
- binds to same receptors as opioid peptides
