Lecture 5- CNS Neurotransmitters Flashcards
list 7 of the most important small molecule neurotransmitters.
acetylcholine, glutamate, GABA, glycine, dopamine, norepinephrine and serotonin
how many different neuropeptides are there and how large are they?
over a hundred
typically 3-36 AA long
how is the concentration of neurotransmitter in the synaptic cleft regulated?
neurotransmitter synthesis, packaging, release and removal
what terminates synaptic transmission?
removal of the NT from the synaptic cleft
where are small molecule and neurotransmitters synthesized and packaged? what implication does this have on replenishment in times of increased demand?
small molecule- in the nerve terminal
neuropeptides- in the soma
small molecules are quickly made to be distributed while it takes longer for peptide synthesis and transport
why can small molecule NT synthesis be called slower than peptide NT synthesis?
because, initially the protein making machinery must be made in the soma and transported to the nerve terminal
describe the structure of an ionotropic neurotransmitter receptor.
ligand gated ion channels that consist of 4 or 5 subunits with 3-4 transmembrane domains each
what causes the diversity of receptors for a single neurotransmitter?
multiple different types of subunits
describe the structure of metabotropic receptors.
they are G protein coupled receptors that are monomeric and contain 7 transmembrane domains
how are metabotropic and ionotropic receptors similar in their effect?
modulation of ion channels
metabotropic receptors modulate ion channels directly or indirectly
what do the different subunits of ionotropic receptors contribute to?
they give the receptor distinct properties
what are the two main contributing factors to diversity of metabotropic receptors?
the receptor type and the G protein that it is coupled to
where is acetylcholine present in the peripheral nervous system?
at the neuromuscular junction and in the synapses of ganglia in the autonomic nervous system
in what two locations is ACh found in the CNS?
in interneurons in the brainstem and forebrain and in large neurons in the basal forebrain that project to the cerebral cortex
what are the four CNS functions of ACh?
in attention, arousal, reward plasticity and enhancing sensory functions upon waking
describe the synthesis and packaging of ACh.
synthesize din nerve terminal from acetyl CoA and choline and packaged into synaptic vesicles by an ACh transporter
what happens to ACh after it is released into the synaptic cleft?
it is cleaved by acetylcholinesterase into acetate and choline. the choline is taken back into the nerve terminal and recycled
what poison inhibits ACh function and how?
organophosphates such as sarin gas inhibits AChE and causes ACh accumulation at the synapse. results in muscle paralysis because the continued depolarization of the postsynaptic cell makes it refractory
which ACh receptors are ionotropic and which are muscarinic? where are they located?
ionotropic- nicotinic; located in the neuromuscular junction and in CNS
metabotropic- muscarinic; in the forebrain and peripheral ganglia of the autonomic nervous system
what are two muscarinic antagonists that can be used therapeutically?
atropine-pupil dilation
scopolamine- for motion sickness
what are the symptoms of myasthenia gravis?
muscle fatigability worsening late in the day and improving with rest, diploplia, ptosis, and difficulty with speaking and swallowing
what is the cause of myasthenia gravis?
antibodies directed against the muscular nicotinic receptors decreasing their quantity
what are three differences of the NMJ in patients with myasthenia gravis?
decreased concentration of ACh receptors, sparese and shallow junctional folds and an expanded synaptic cleft
what is the effect myasthenia gravis on muscle function?
decreases the size of MEPP and EPP’s, decreases the probability of muscular action potential. the action potential decreases in size during repeated stimulation
what are four treatments of myesthenia gravis?
cholinesterase inhibitors, thymectomy, corticosteroids and immunosuppressants
what is the most prominent transmitter for normal brain function?
glutamate
what problem can glutamate cause to neurons?
can cause excitotoxicity which can excite a neuron to death
when is excitotoxicity most often seen? what can be used to prevent it?
thought to cause damage during stroke when oxygen deprivation slows glutamate reuptake. may be treated with glutamate receptor antagonists in the future
what is glutamate synthesized from and where? why is it not just transported into the cell?
synthesized from glutamine or by the transamination of alpha ketoglutarate in the nerve terminal. glutamate cannot cross the blood brain barrier
what happens to glutamate after it is released into the synapse?
it is removed by high affinity transporters in the nerve terminal and nearby glial cells. the glial cells convert the glutamate back into glutamine and transport it back into the nerve terminal
what are the three different types of ionotropic glutamate receptors? what types of channels are they?
NMDA, AMPA and kainate
they are excitatory Na+ channels
what is unique about NMDA receptors?
Ca++ can pass through, ion flow is ligand and voltage dependant because of the Mg++ blocking entry and glycine is also required to open the channel
what is the result of metabotropic activation by glutamate?
either activation or inhibition of the postsynaptic cell
what are the major inhibitory transmitters in the CNS? where are they primarily used?
GABA is widely distributed in the brain and within the interneurons and purkinje cells of the cerebellum.
glycine is used at synapses in the spinal cord predominantly
where is GABA synthesized and what does it require?
it is synthesized in nerve terminals from glutimate
requires pyridoxal phosphate (PLP) derived from vitamin B6
how is GABA removed from the synaptic cleft?
it is removed by transporters on the nerve terminal and nearby glial cells. GABA-T then returns it to glutamine
what does decreased GABA function cause?
epilepsy
what is glycine synthesized from and what transporter does it share with GABA?
it is synthesized from serine and packaged into vesicles by the vesicular inhibitory amino acid transporter (same as GABA)
how is glycine removed from the synapse and what is a consequence of its failure?
removed into nearby glia and the nerve terminal
excess synaptic glycine causes neonatal disease with lethargy and mental retardation
what are the ionotropic and metabotropic GABA receptors?
ionotropic- GABA a and GABA c
muscarinc- GABA b
what types of channels are GABA and glycine receptors?
inhibitory chloride channels
what are two GABA receptor agonists and what are they use for?
benzodiazopine is used as a tranquilizer
barbiturates are used as anesthetics to control epilepsy
what is a glycine receptor antagonist and what does it do?
strychnine (used in rat poison)- causes over activity in the spinal cord and brainstem leading to seizures
what is the distribution of expression of GABA and glutamate receptors and synthesizing molecules?
both are expressed broadly across the brain
what is the distribution of expression of Dopamine, Norepinephrine and Serotonin receptors and synthesizing molecules?
the receptors are widely distributed while the synthesizing machinery is only expressed in localized regions
what are the three catecholamines and what other neurotransmitters are part of the group of biogenic amines?
catecholamines: dopamine, epinephrine and norepinephrine
rest: histamine and serotonin
what is the main function of aminergic neurons?
to help modulate the intensity of more specific neuronal signals- only used by a few neurons in the brain
what transporter packages biogenic amines and where are they removed to after use?
vesicular monoamine transporter
reuptake into nerve terminals
what type of receptors do biogenic amines utilize and what is the exception?
metabotropic
serotonin also has ionotropic receptors
describe catecholamine synthesis.
tyrosine->DOPA->dopamine->NE->epinephrine
describe serotonin synthesis.
tryptophan-> 5-hydroxytryptophan->serotonin
where are dopamine containing neurons and what are their functions?
substantia niagra->striatum: coordination of body movements
midbrain (ventral tegmental area->ventral parts of striatum): involved in motivation, reward and reinforcement
projections to the cortex (minor): emotional behavior
what type of neurons degenerate in Parkinsons and what is it treated with?
dopamine neurons in the substantia nigra and they are treated with L-DOPA (precursa to dopa)
what do addictive drugs such as cocaine do?
raise dopamine levels by interfering with reuptake
where are NE containing neurons in the CNS and PNS and what is the function?
CNS: from the locus coeruleus- influences sleep and wakefulness, attention and feeding
PNS: sympathetic ganglion cells- transmitter of synaptic motor system
what type of receptors do catecholamines use?
metabotropic
what do dopamine receptors do and what are antagonists used for?
they activate or inhibit adenylyl cyclase
antagonists used as anti-emetics
whaqt are antagonists and agonists of norepinephrine used for and where do they have effect?
they are used for cardiac arrhythmias and migraine headaches and they are mediated by receptors in smooth muscle
how are catecholamines removed from the synaptic cleft?
by using transmitter specific plasma membrane transporters into nerve terminals and glia
what is the effect of amphetamine?
it inhibits both dopamine and norepinephine transporters
where are serotonin containing neurons and what do they do?
in the raphe nuclei projecting to the forebrain and brainstem
implicated in regulation of sleep, eating, arousal and wakefullness
what transporter reuptakes serotonin? what is it inhibited by?
SERT
SSRIs
what are metabotropic serotonin receptors implicated in?
emotions, circadian rhythms, motor behaviors and mental arousals.
impaired in psychiatric disorders
activation mediates satiety
describe ionotropic serotonin receptors and what is one reason a drug would target them?
non selective excitatory cation channels
target for drug to prevent nausea
what do antipsychotic drugs do?
block dopamine receptors because excess dopamine release may cause some psychotic illnesses
what is the goal of two subtypes of anti-anxiety drugs?
MAO inhibitors block breakdown of biogenic amines
some are inhibitors of serotonin reuptake
what are the three classes of antidepressants?
MAO inhibitors that block the breakdown of biogenic amines
tricyclic antidepressents block reuptake of serotonin and NE
serotonin reuptake inhibitors act on serotonin transporters specifically
what effects do peptide neurotransmitters have? what is their biological activity dependent upon?
modulate emotions, change pain perception and responses to stress
dependent upon the amino acid sequence
what are the five categories of peptide neurotransmitters?
brain-gut peptides, opioid peptides, pituitary peptides, hypothalamic releasing peptides and miscellaneous peptides
describe the synthesis and processing of neuropeptides.
synthesized in ER and processed there. final processing into active peptides occurs in the vesicles after they bud off of the Golgi (multiple different active peptides)
describe the release and removal of neuropeptides from the synaptic cleft.
coreleased with small-molecule neurotransmitters and removed from the cleft via degradation by peptidases
what sometimes happens to peptide NTs within the synaptic cleft?
they are degraded to more active peptides
what is the affinity of peptide receptors?
they are activated at relatively low peptide concentrations
where are opioid peptides and what are their functions?
wide distribution throughout brain
tend to be depressants and can act as analgesics
what is morphine and what does it do?
it is an opioid that is an analgesic
it binds to the same receptors as opioid peptides
