lec 6 - neurotransmission Flashcards
Synaptic Transmission
An action potential must reach the axon terminal with sufficient current to open voltage-gated Ca2+ channels, which are essential for neurotransmitter release
synaptic transmission process:
1) Ca2+ enters neuron
2) binds to synaptic vesicles
3) vesicles fuse with plasma membrane
4) neurotransmitter is released into synaptic cleft via exocytosis
5) neurotransmitter binds to receptor on postsynaptic cell
chemical synapse - steps of synaptic transmission
1) neurotransmitters are synthesized and stored in vesicles
2) action potential arrives at presynaptic terminal
3) voltage-gated Ca2+ channels open, influx of Ca2+
4) Ca2+ allows vesicle docking and neurotransmitter release
5) neurotransmitter binds to receptors - causing channels to open (or close)
6) excitatory (or inhibitory) postsynaptic potential is generated
7) vesicular membrane is retrieved from plasma membrane
8) neurotransmitter is removed by glial uptake (or enzymatic degradation)
Neurotransmitter Receptors
Ionotropic receptors
Metabotropic receptors
Ionotropic receptors:
allow a specific ion to flow through the receptor
Directly promotes or inhibits an action potential
Rapid and short duration responses
Metabotropic receptors:
involve 2nd messenger systems (cAMP, cGMP, or DAG and IP3)
Indirectly promotes or inhibits an action potential
Not rapid but lasts longer in duration
Ionotropic receptors steps:
1) nicotinic ACh receptor channel activation
2) membrane depolarization
3) action potential excitation
4) muscle contraction
Metabotropic receptors steps:
1) muscarinic ACh receptor activation
2) release of alpha-GTP and By from heterotrimeric G protein
3) activation of inward rectifier K+ channel by By
4) membrane hyperpolarization
5) decrease in heart rate
Acetylcholine
> excitatory neurotransmitter
involved in movement and cognition,
memory, motivation, alertness, and attention
Acetylcholine binds to ___ receptors on the ____ cell
cholinergic
postsynaptic
Acetylcholine is degraded in the synaptic cleft by ____
acetylcholinesterase (AChE)
> Clinical note: anticholinesterases block AChE activity to treat myasthenia gravis
Acetylcholine (ACh) is a small molecule neurotransmitter assembled in the axon terminal from ______
acetyl-coenzyme A (acetyl-CoA) and choline
Acetyl-CoA is produced from ____ and choline is from ____
glycolysis
diet (foods high in choline include eggs, meats, beans, and leafy green vegetables)
> the enzyme choline acetyltransferase (ChAT) catalyzes this reaction
ChAT is a specific marker for ___. The availability of dietary choline is the limiting factor for _____
cholinergic neurons
ACh synthesis
Ach is then transported into vesicles and stored there until an action potential stimulates_____. It is then released into the ____ by _____.
Ca2+ -dependent release
synaptic cleft
exocytosis
Neurological disorders caused by too little ACh can be treated with drugs that:
inhibit AChE
> so that ACh stays in the synaptic cleft for a longer period of time
Myasthenia gravis =
> chronic autoimmune disorder
weakness
rapid fatigue of voluntary skeletal muscles
> acetylcholine is released into the synaptic cleft
> receptors on the postsynaptic membrane are disrupted
Myasthenia gravis treatment =
> anticholinesterase medications
inhibit acetylcholinesterase
prevent the breakdown of acetylcholine in the synaptic cleft
Acetylcholine in the CNS
Cholinergic neurons in the CNS
> Basal forebrain
> Upper brainstem
Basal forebrain =
Cholinergic neurons from nucleus basalis in the basal forebrain
Project to cerebral cortex and limbic system
Involved in attention, motivation, and memory
Upper brainstem =
Project to basal ganglia, thalamus, hypothalamus, medulla, and cerebellum
Involved in cortical arousal, alertness, and movement
In the CNS, cholinergic neurons have a more limited role than in the PNS. There are two major regions of the brain that contain cholinergic neurons:
> nucleus basalis in the basal forebrain
> pedunculopontine tegmental nuclei and laterodorsal tegmental nuclei in the brainstem (specifically, at the junction of midbrain and pons)
The cholinergic neurons in nucleus basalis die in ____ due to the development of:
Alzheimer’s disease
> neurofibrillary tau protein tangles
beta-amyloid plaques
Patients with Alzheimer’s are treated with AChE inhibitors to keep ACh in the synaptic cleft
Acetylcholine in the PNS
Acetylcholine is the major efferent NT of the PNS
Released at neuromuscular junctions (NMJ) by lower motor neurons that innervate skeletal muscles
Released at autonomic nervous system synapses by parasympathetic preganglionic and postganglionic neurons and by sympathetic preganglionic neurons
___ is the most abundant neurotransmitter in the nervous system
Acetylcholine
found at:
> neuromuscular junctions
> preganglionic parasympathetic and sympathetic synapses
> postganglionic parasympathetic synapses.
Glutamate
> primary excitatory NT
most abundant NT in the CNS
causes depolarization of the postsynaptic cell
increasing the likelihood of action potential firing
If too much glutamate is released, it can induce ____
seizures and epilepsy (more than two seizures)
Neurons uptake glutamate via _____; however, ____ play a more critical role in glutamate synthesis
specific excitatory amino acid transporters and repackage it into vesicles for release
astrocytes
Astrocytes and glutamate:
> uptake glutamate via excitatory amino acid transporters
convert the glutamate into glutamine via the addition of ammonium
> removes potentially toxic ammonium from the interstitial fluid
glutamine is then transported to the neuron where it is converted back into glutamate
if the excitatory amino acid transporters are blocked or the enzyme that converts glutamine into glutamate is decreased =
glutamate and ammonium may reach toxic levels and cause neuronal death
Glutamate Receptors
There are four major glutamate receptor subtypes:
> three are ionotropic
> one is metabotropic
The three ionotropic receptors are:
> AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
> NMDA (N-methyl-D-aspartate)
kainate
> gate sodium inward and potassium outward
increase the positive sodium charge intracellularly, they directly activate action potential initiation
Ionotropic glutamate receptors =
> AMPA and NMDA are the 2 major ionotropic glutamate receptors
> NMDA receptor antagonists: ketamine and memantine
> Clinical uses: anesthetics, antidepressants, and Alzheimer’s disease treatment
The NMDA receptor is unique in that it also allows for ___ influx.
calcium
NMDA receptor antagonists/inhibitors:
> ketamine and memantine
Ketamine =
> dissociative anesthetic
> some forms of it may also be used in the treatment of depressive and mood disorders
Memantine =
> used in Alzheimer’s treatment
glutamate mediated neurotoxicity (basically, overactivation of glutamate or too much glutamate) is one of the factors in the pathogenesis of Alzheimer’s disease
> binds to NMDA receptors
blocking and preventing glutamate from binding
improve cognitive and memory deficits associated with Alzheimer’s disease
Metabotropic glutamate receptor =
> mGluR
various subtypes that function as G-protein-coupled receptors (GPCRs)
> serve diverse functions in the CNS and in the PNS
learning/memory, anxiety, and pain
The NMDA receptor channel pore =
is blocked by Mg2+, which prevents Na+ and Ca2+ influx
Glutamate binding to AMPA receptors allows ___ influx and a local ___ that displaces ___ from the NMDA receptor
Na+
depolarization
Mg2+
> This allows Na+ and Ca2+ influx through the NMDA receptor, which leads to action potential generation
Substance P =
> excitatory neuropeptide
synthesized in CNS and PNS neurons
> Released by primary afferent neurons in the spinal cord and brainstem
> Signals ascending pain transmission by synapsing in the substantia gelatinosa
> Promotes local inflammatory response (i.e., vasodilation and mast cells)
> Often co-released with glutamate to enhance effects of glutamate
Substance P is a peptide neurotransmitter that is released by ___ neurons in the ____
pseudounipolar
spinal cord and brainstem
The peripheral process of the pseudounipolar neuron releases substance P to promote vasodilation at the site of an injury =
which promotes immune cells to release histamine to cause a red flare response at the injury (to protect that area from further injury)
central process of the pseudounipolar neuron releases substance P onto the spinal cord to transmit pain signals from the periphery.
Substance P neurons terminate in the ____. This region contains projection neurons that will convey pain information up to the brain as well as interneurons that release the endogenous opioid ____.
substantia gelantinosa of the dorsal horn of the spinal cord
enkephalin
GABA
> primary inhibitory NT in the CNS (particularly in the brain)
> causes hyperpolarization of the postsynaptic cell
decreasing the likelihood of action potential firing
GABA is the most abundant neurotransmitter in the:
cerebrum, cerebellum, and upper brainstem
Glycine is another inhibitory neurotransmitter that is mainly located in:
the lower brainstem and in the spinal cord
Inhibitory neurotransmitters decrease the probability that the post-synaptic neuron fires an action potential because:
it hyperpolarizes the cell due to the influx of chloride or efflux of potassium
GABA is made from glutamate using the enzyme glutamic acid decarboxylase (GAD)
> GAD is a specific marker for GABAergic neurons
> economic way of synthesizing neurotransmitters
> If a neuron is going to be excitatory it only needs the enzyme to make glutamate (glutaminase), but with one extra enzyme (GAD), the cell makes GABA
> Neurons either release glutamate or GABA but can NOT release both
GABAA receptors (ionotropic):
> hyperpolarize neuron via Cl- influx
> Agonists: benzodiazepines, zolpidem, and barbiturates
> Clinical uses: anxiolytics, sedatives, muscle relaxers, and epilepsy treatment
GABAB receptors (metabotropic):
> hyperpolarize neuron via GPCRs that lead to K+ efflux
> Agonist: baclofen
> Clinical uses: muscle relaxers
GABA causes inhibition of neurotransmission by promoting ___.
hyperpolarization
There are two major GABA receptors that gate different ions:
> GABAA receptors and GABAB receptors
Glycine
> major inhibitory NT (particularly in the spinal cord)
> binds to receptors on the postsynaptic cell
> Glycine receptors hyperpolarize the neuron via Cl- influx
___ is the primary inhibitory neurotransmitter in the spinal cord and the lower brainstem
Glycine
> Similar to GABAA receptors, glycine receptors cause hyperpolarization via chloride influx
Glycinergic Renshaw Cells
> Renshaw cells are glycinergic interneurons
> in the spinal cord
> regulate motor neuron firing
⍺-motor neuron collateral branches synapse on Renshaw cells, causing Renshaw cells to release glycine onto the ⍺-motor neurons as a local feedback inhibition to reduce firing and limit muscle contraction
Renshaw cells are glycinergic neurons in the ___ of the spinal cord that regulate ____
ventral horn
motor neuron firing
Renshaw cells receive ____ that activate the Renshaw cell to release glycine onto the same alpha motor neurons as a feedback inhibition to reduce firing and decrease muscle contraction.
alpha motor neuron collateral branches
Opioid Peptides: Endorphins and Enkephalins
> endogenous opioids that bind to opioid receptors and have analgesic effects (i.e., pain relief)
> s exert pre-synaptic inhibition of substance P release by primary afferent neurons in the substantia gelatinosa = preventing pain signal transmission
β-Endorphin: synthesized in ____
pituitary gland
Enkephalins: synthesized in ____
spinal cord
µ receptors (opioid receptors)
β-endorphin and enkephalins are endogenous ligands
Binding inhibits release of substance P to inhibit pain transmission
Agonists: morphine
Clinical uses: pain relief
Endocannabinoids
> inhibitory retrograde neurotransmitters
> Agonist: THC in cannabis
> Involved in memory, pain modulation, and reward
____ are major endocannabinoids
Anandamide and 2-AG
> bind to cannabinoid receptors (CB1 and CB2), which are metabotropic receptors that function as GPCRs, on the presynaptic cell
> Binding inhibits neurotransmitter release
Dopamine
> modulatory neurotransmitter
involved in movement, reward, and cognition
> released from the substantia nigra and ventral tegmental area in the brainstem
> project to the basal ganglia, limbic areas, and the prefrontal cortex
Dopamine receptors: bind dopamine
D1 and D2 receptors (both function as GPCRs)
> DA binding to D1 = stimulatory = promotes movement
> DA binding to D2 = inhibitory = inhibits movement
Dopamine - clinically
Agonists and clinical uses: Parkinson’s disease treatment
Antagonists and clinical uses: schizophrenia and bipolar disorder treatment
Dopamine reuptake inhibitors: depression, ADHD, and substance use disorder treatment
Norepinephrine/Noradrenaline
> modulatory neurotransmitter involved in alertness and mood
> released from locus coeruleus in the brainstem
> Noradrenergic neurons project to widespread CNS areas
Adrenergic receptors:
class of GPCRs that bind noradrenaline/ norepinephrine
Too little NE is associated with ___, while too much NE is associated with ___.
depression
mania
> When there is too much NE, NE receptors are internalized, so they are not being overly stimulated, which leads to too little NE, which can cause depression. Thus, repeated cycles of mania and depression can occur, which is called bipolar depression.
Serotonin
> modulatory neurotransmitter involved in sleep, mood, and pain modulation
> released by raphe nuclei in the brainstem
> Serotonergic neurons project to widespread CNS areas
> There are several subtypes of serotonin receptors, which all function as GPCRs
Selective serotonin reuptake inhibitors (SSRIs): antidepressants
Serotonin is the precursor to ____
melatonin
