Principles of Chemical Synaptic Transmission
What are the two serotonin autoreceptors? Where are they located and what are their effects?
1) 5-HT1A receptor; cell body; inhibits cell firing 2) 5-HT1D receptor; nerve terminals; inhibits release and synthesis of serotonin
How do G protein-coupled receptors operate?
1) G proteins exist as heterotrimers in the basal state, with the alpha subunit bound to GDP 2) When the receptor is activated by its ligand, it associates with the alpha subunit and causes the subunit to bind to GTP rather than GDP 3) GTP binding causes the dissociation of the alpha subunit from the beta-gamma subunits. The alpha and the beta-gamma subunits are then free to activate a variety of effector proteins. 4) The alpha subunit has intrinsic GTPase activity which removes the phosphate group from GTP. This causes the re-association of alpha and beta-gamma subunits
What are the 3 major effectors of Gi?
1) Inhibition of AC via Gi-alpha 2) inhibition of voltage-gated Ca2+ channels via beta-gamma subunits 3) Activation of a certain type of K+ channel via beta-gamma subunits
What is the criteria to identify a neurotransmitter?
1) Localization: substance synthesized and stored in presynaptic neuron 2) Release: substance must be release by presynaptic neuron upon stimulation 3) Synaptic mimicry: the substance, when applied exogenously, must produce a response in the postsynaptic neuron that mimics the response produced by stimulation of the presynaptic neuron 4) Synaptic pharmacology: the substance should act on specific receptors on the postsynaptic neuron. If the action of a synaptically released substance is blocked by a known receptor antagonist, the identity of the neurotransmitter is strongly suggested.
Why is it necessary to have multiple neurotransmitters?
1) Multiple afferents terminate on a single postsynaptic neuron. 2) A single presynaptic neuron can release multiple neurotransmitters, allowing information to be coded by different firing patterns. 3) Different transmitters are released from different sites on the neuron. 4) Postsynaptic responses to different transmitters occur at different time scales. 5) Different transmitters are depleted at different rates.
Explain the cAMP second messenger cascade.
1) NE binds to the beta-adrenergic receptor, activating the stimulatory G protein (Gs) 2) The alpha subunit of Gs activates the enzyme adenylyl cyclase 3) Adenylyl cyclase converts ATP into the second messenger cAMP. 4) cAMP activates the enzyme PKA 5) PKA phosphorylates a K+ channel to induce its closure, leading to depolarization
What are the basic requirements of chemical synaptic transmission?
1) Neurotransmitter synthesis and storage 2) Neurotransmitter release 3) Neurotransmitter receptors and effectors 4) Neurotransmitter recovery and degradation
What features of a cholinergic synapse distinguish it from a monoamine synapse?
1) Vesicular transporter for ACh is distinct from VMAT 2) The termination of synaptic actions of ACh occur via rapid enzymatic breakdown, not reuptake. 3) The reuptake transporter does not return neurotransmitter to terminal, but instead recycles choline. 4) Mitochondria in the terminal supply acetyl CoA necessary for ACh synthesis. 5) Both G protein-coupled receptors and ligand-gated ion channels mediate postsynaptic actions.
What are the two types of hyperekplexia?
1) a mutation of a gene for the glycine receptor causes the chloride channel to open less frequently when exposed to glycine; seen in people and mutant mice called spasmodic 2) fewer glycine receptors are expressed than normal; seen in cattle and mutant mice called spastic
What are some general properties of signal transduction pathways?
1) amplification 2) specificity 3) divergence (single signal generates multiple responses) 4) convergence (signals interact with each other) 5) capacity to induce long-lasting changes
How is adenylyl cyclase both activated and inhibited by NE? What is this an example of?
1) binding of NE to beta-AR activates Gs and causes activation 2) binding of NE to alpha2-AR activates Gi and causes inhibition antagonistic convergence
Name 2 psychostimulants and explain what they do.
1) cocaine: blocks DAT, NET, and SERT 2) amphetamine: serves as a substrate of DAT, NET, and SERT causing catecholamines to be pumped out of terminal via reverse transport through transporters
Why are mechanisms that terminate transmitter action necessary?
1) continuous transmitter action will not provide postsynaptic neurons with information about firing pattern of presynaptic neuron 2) Unrestrained Ca2+ entry through Ca2+-permeable transmitter-gated channels will lead to cytotoxicity 3) Limits the diffusion of transmitter molecules to neighboring synapses, enabling a point-to-point information transfer. 4) reuptake allows for recycling and reuse of unmetabolized transmitter
What are the two ways in which g protein-coupled receptors can facilitate signal transduction?
1) g protein can directly regulate an ion channel 2) g protein can trigger intracellular second messenger cascades and the regulation of protein phosphorylation
How are classic transmitters different from peptide transmitters?
1) location of synthesis -> neuropeptide synthesized in cell body while DA is synthesized in the nerve terminal 2) storage vesicle ->neuropeptides are stored in large dense core vesicles, whereas DA is stored in small clear synaptic vesicles 3) clearance from synapse -> DA is quickly transported back into terminal while peptides are terminated slowly by peptidases
What are the important functional consequences of transporter-mediated reuptake?
1) reuptake limits the duration of receptor activation 2) it limits the diffusion of transmitters to other synapses 3) it allows for the recycling of unmetabolized transmitter
Explain the effects of the alpha subunit of the g protein Gq.
1) stimulates enzyme phospholipase C (PLC) 2) PLC acts on membrane phospholipid PIP2, splitting it into the two second messengers DAG and IP3 3) DAG stimulates downstream enzyme protein kinase C (PKC) 4) IP3 stimulates the release of Ca2+ from intracellular stores of Ca2+
Dense-core vesicles (secretory granules)
100 nm vesicles containing soluble proteins and peptides
What are the different types of 5-HT receptors?
5-HT1: Gi-coupled (inhibits AC) 5-HT2: Gq-coupled (activates PLC) 5-HT4, 5-HT6, 5-HT7: Gs-coupled (activates AC) 5-HT3 receptor: 5-HT-gated ion channel
What receptor does LSD act on? Is it an agonist or an antagonist?
5-HT2A receptor agonist
Synaptic vesicles
50 nm vesicles containing amino acid and amine neurotransmitters
Why is L-dopa a preferrable treatment for Parkinson's rather than a D2 agonist?
A D2 agonist would affect the whole brain and if you increase L-dopa, it will be better for maintaining the timing of dopamine neurons firing
What is hyperekplexia?
A condition in which the victim experiences an involuntary and exaggerated startle response which does not adapt when the stimulus is repeated
What are neurotrophins?
A family of neurotrophic factors that signal via Trk receptors, a family of tyrosine kinases that have PTK domain in the receptor itself
What is autocrine transmission of neurotrophic factors?
A neurotrophic factor acts on the neurons that release it
What is paracrine transmission of neurotrophic factors?
A neurotrophic factor released from a neighboring cell acts on many nearby neurons in the absence of formal synaptic connections
What is anterograde transmission of neurotrophic factors?
A neurotrophic factor released from the terminals of a nerve cell acts on the synaptic targets of these terminals.
What is protein phosphorylation?
A process by which an enzyme called protein kinase adds a phosphate group to a protein
What is POMC?
A propeptide that is a precursor of several bioactive neuropeptides
Explain the process of neurotransmitter release.
A synaptic vesicle loaded with neurotransmitter releases its contents into the synaptic cleft by means of exocytosis (the fusion of the vesicle membrane with the presynaptic membrane) in response to the influx of Ca2+ through voltage-gated Ca2+ channels. The synaptic vesicle is then recycled by the process of endocytosis.
What is the classic model of action of neurotrophic factors?
A target-derived neurotrophic factor acts on innervating nerve terminal
What is myasthenia gravis? What is it caused by? How do you treat it?
A type of autoimmune disorder characterized by muscle weakness and fatigue. It is caused by the development of autoantibodies to muscular nAChRs, which prevents ACh interaction with them. Treatment involves administration of AChE inhibitors (anticholinesterases) which prolong the duration of ACh in the synapse.
What is the blood-brain barrier?
A wall of endothelial cells in the brain that form tight junctions and do not allow for passive diffusion.
What neurotransmitter mediates fast synaptic transmission at neuromuscular junctions?
ACh
Explain how NGF promotes the survival of cholinergic neurons.
ACh released from septal nerve terminals activates hippocampal neurons, causing an increase in the synthesis and release of NGF. NGF then acts on nerve terminal to promote survival of cholinergic neurons.
What type of receptor does glutamate usually use to communicate?
AMPA receptors
What are the three subtypes of the glutamate receptor? What are they named after? What ion are they all permeable to?
AMPA, NMDA, and kainate; their selective agonists; Na+
Cell Theory
All tissues are composed of microscopic units called cells.
How do amine and amino acid transmitters get transported to the terminal?
Amine and amino acid transmitters are synthesized locally at the terminal and then loaded into synaptic vesicles via vesicular transporter proteins
What are the catecholamines?
Amine neurotransmitters that contain a catechol group; dopamine, norepinephrine, epinephrine
What is the key difference between amino acid/amine transmitters and peptide transmitters?
Amino acid and amine transmitters are locally synthesized at the nerve terminal, so can be rapidly replenished. Peptide transmitters are synthesized in the cell body so they can be rapidly depleted.
What is phencyclidine? How might it relate to schizophrenia?
Angel dust, a non-competitive NMDA receptor antagonist; This drug causes many similar effects to the symptoms of schizophrenia, influencing scientists to start considering the glutamate hypothesis of schizophrenia
Explain the end-product inhibition of TH.
As catecholamine release decreases, catecholamine concentration in the cytosol of the terminal increases, and TH activity decreases.
What are autoreceptors and how do they work?
Autoreceptors represent a negative feedback mechanism that dampen the firing rate of cells and reduce the release of neurotransmitters via activation of K+ channels
What ion are kinases typically sensitive to?
Ca2+
What other ion is NMDA receptors permeable to?
Ca2+
Explain the process in which glutamate causes excitotoxicity.
Ca2+ leaks into the cells. The entry of Ca2+ triggers the synaptic release of glutamate. Glutamate further depolarizes neurons which further raises intracellular Ca2+ and causes still more glutamate to be released
Explain Huntington's Disease pathology. What is a common treatment for this disease?
Characterized by degeneration of GABAergic projection neurons in the striatum (caudate and putamen). It is commonly treated with dopamine receptor antagonists that block the inhibitory dopaminergic inputs to GABAergic projection neurons.
What type of channel does the GABA(A) receptor gate?
Cl-
What type of channel does the glycine receptor gate?
Cl-
Cell body (soma)
Contains the nucleus and is the site of gene transcription
What are the 2 types of dopamine receptors? What G protein are they coupled to?
D1-like: Gs coupled D2-like: Gi coupled
First generation anti-psychotic drugs are antagonists of what receptor?
D2-like
What are the catecholamine transporters? Describe their substrate specificity.
DAT (dopamine transporter) and NET (norepinephrine transporter); They both have poor substrate specificity and will both transport DA or NE, with NET having a higher affinity for DA than NE
Electrical synapses
Exist in mammals, but are more common in invertebrates where they are found between sensory and motor neurons in neural pathways mediating escape reflex.
What are superfamily do all catecholamine receptors belong to?
G protein-coupled receptor
What two types of G protein-coupled muscarinic receptors are there?
Gq and Gi
What was the first g protein to be discovered?
Gs
What are the major degradation products of catecholamines?
HVA, VMA, and MHPG
How are glutamate-gated channels coincidence detectors? What is significant about this?
In order for ionic current to flow through the NMDA-gated channel, both glutamate and depolarization must coincide. This makes Glutamate-gated channels important for synaptic integration in the CNS and the associative form of learning.
What is a g protein-coupled receptor? What type of synaptic transmission does it mediate?
It is a protein that does not span the membrane. The transmitter binds to the receptor, whose activated form activates g proteins which go on to activate effector proteins. They mediate slow synaptic transmission
What can enter through the blood brain barrier?
Lipophilic molecules and hydrophilic molecules that are transported by an ATP-dependent process
What is one type of drug that has been used to treat atypical depression? What are the risks? Explain why these risks are present.
MAO Inhibitors; hypertensive crisis; MAO is present in the gut and liver as well as the brain. In the gut and liver, MAO catabolizes biogenic amines. When MAO is inhibited, however, these biogenic amines are taken up into sympathetic nerve terminals by NET and causes a massive release of NE
What enzyme degrades serotonin? What is its metabolite?
MAO; 5-HIAA
What are the two major subtypes of ACh receptors?
Muscarinic: G protein-coupled Nicotinic: ligand-gated ion channels
What are some examples of Gq-coupled neurotransmitter receptors?
NE: a1-adrenergic Serotonin: 5HT2 ACh: muscarinic (M1, M2, M3)
What type of receptor mediates fast synaptic transmission at the neuromuscular junction?
Nicotinic ACh receptors
When a benzodiazepine alone binds to a GABA(A) receptor, what happens?
Nothing. Benzos and barbiturates only cause channels to open more when GABA is present
How do peptide neurotransmitters get transported to the terminal?
Peptide neurotransmitters are synthesized and packaged into secretory granules in the cell body and then transported to the terminal
How can you increase the amount of catecholamines in the brain? Why will administering dopamine and tyrosine be ineffective?
Peripheral administration of L-dopa will increase brain catecholamines because dopa decarboxylase activity is very high. Dopamine cannot cross the blood-brain barrier. Tyrosine is ineffective because TH is saturated by circulating levels of tyrosine.
Dendrites
Primary site of synaptic contact and receives most of the incoming synaptic information
How do neurotrophic factors work?
Produce effects by activation of protein tyrosine kinases which phosphorylate proteins on tyrosine residues
How are tricyclic antidepressants different from psychostimulants?
Psychostimulants act strongly on DAT which is critical for their stimulant and addictive properties. Tricyclics, on the other hand, have a weak affinity for DAT.
What determines which catecholamines are expressed in a given neuron?
Region specific expression of the synthetic enzymes
What is reserpine?
Reserpine is an antihypertensive agent that causes a side effect of severe depression. It inhibits vesicular transport of monoamines (VMAT) and induces their depletion in the synapse.
What transporter mediates serotonin reuptake? Name a drug that targets this transporter.
SERT; SSRI
Electrical hypothesis
Synaptic transmission is simply electrical current flowing from one neuron to the next.
What are diffuse modulatory systems?
Systems in which the cell bodies are confined to a small number of discrete brain areas, but their axons project widely throughout the CNS. These diffuse modulatory systems perform regulatory functions via G protein-coupled receptors and second messenger cascades.
What is the rate-limiting enzyme in catecholamine synthesis?
TH
Give an example of a shortcut pathway and explain it.
The muscarinic ACh receptors in the heart; The activated beta-gamma subunit of inhibitory G protein (Gi) directly opens the K+ channel and causes hyperpolarization, decreasing the heartrate
Synaptic transmission
The process of information transfer at a synapse.
What is the function of presynaptic metabotropic glutamate receptors?
They act as inhibitory autoreceptors which cause inhibition of transmitter release via inhibition of voltage-gated Ca2+ channels
What is a transmitter-gated ion channel and what type of synaptic transmission does it mediate?
They are membrane-spanning proteins with a central ion-permeable pore that opens upon neurotransmitter binding; mediate fast synaptic transmission
What are shortcut pathways? How fast are these pathways?
They are the fastest of the g protein-coupled receptor-mediated pathways. Responses begin within 100-300 msec of neurotransmitter binding to the receptor
How are antidepressants and psychostimulants related to neurotransmitter removal?
They interfere with the uptake of monoamines to increase their synaptic levels and prolong their action
Generally speaking, how do anesthetic drugs work?
They over-activate GABA(A) receptors
Axon
Transmits outgoing information from the soma and often has multiple branches, the terminals of which form synapses with the dendrites and cell bodies of other neurons
What amino acid are all catecholamines derived from?
Tyrosine
What are the steps in the formation of the three catecholamines?
Tyrosine --(tyrosine hydroxylase)--> L-dopa --(Dopa decarboxylase)--> Dopamine --(Dopamine beta-hydroxylase)--> NE --(Phentolamine N-methyltransferase)--> Epinephrine
What is VMAT?
Vesicular Monoamine Transporters; they put monoamines into synaptic vesicles
What is signal transduction?
What happens inside the cell; the cascades of biochemical reactions by which cells translate various extracellular signals into appropriate cellular responses
What was the first molecule to be identified as a neurotransmitter? From where is it released? What has it been implicated in?
acetylcholine; a small number of neurons in the brain and local interneurons in the striatum; learning and memory, control of movement, and mood
Which two receptors serve as autoreceptors?
adrenergic a2 receptors and dopaminergic d2 receptors
What are the 3 types of adrenergic receptors? What G protein are they coupled to? What does that G protein activate?
alpha 1: Gq-coupled; activates PLC alpha 2: Gi-coupled; inhibits AC beta: Gs-coupled; activates AC
Where is ACh synthesized and how is it put into synaptic vesicles?
at the nerve terminal; concentrated in synaptic vesicles by a vesicular ACh transporter
What drugs can bind to GABA(A) receptors and modulate their function?
benzodiazepines and barbiturates
What classes of drugs can bind to their own distinct sites on the GABA(A) channel? What do they do?
benzodiazepines and barbiturates; enhance the GABA(A) channel and result in stronger inhibitory synaptic transmission (reduced consciousness, inhibition of seizures)
What are the monoamines?
catecholamines and serotonin
What drugs are used to boost cholinergic transmission in Alzheimer disease?
central-acting anticholinesterases
What enzyme is responsible for ACh synthesis? What specifically does it do?
choline acetyltransferase (ChAT); transfers an acetyl group from acetylcoenzyme A to choline
What is the rate-limiting step in ACh synthesis?
choline transport
Postsynaptic density
contains neurotransmitter receptors which convert the intercellular chemical signal to an intracellular signal in the postsynaptic neuron
Where are TH and dopa decarboxylase found? Where is DBH found? What does this tell you about where each of the catecholamines are produced?
cytosol; synaptic vesicles; DA is produced in the cytosol and then transported into synaptic vesicles by vesicular monoamine transporters. There it can be converted to NE and Epinephrine
What is the root cause of many brain disorders?
defective synaptic transmission
How can the increased activity of GABAergic projection neurons caused by dopamine deficiency in Parkinson's disease be corrected?
dopamine agonists or muscarinic antagonists
How are peptides removed from the synapse?
enzymatic degradation and the passive diffusion
What is the general structure of a g protein-coupled receptor?
extracellular transmitter-binding sites, 7 trans-membrane elements, intracellular G protein-binding sites; alpha, beta, and gamma subunits
How is Acetylcholine removed from the synapse?
first enzymatic degradation, then reuptake
What type of receptor usually mediates slow synaptic transmission?
g-protein coupled receptors
What neurotransmitter has the most amount of transporters?
glutamate
What amino acids mediate fast synaptic transmission in the CNS?
glutamate, GABA, and Gly
What neurotransmitter mediates most of the fast excitatory synaptic transmission in the brain? What about fast inhibitory synaptic transmission?
glutamate; GABA and, to a lesser extent, glycine
What is the precursor and key synthesizing enzyme for GABA?
glutamate; glutamic acid decarboxylase (GAD)
What is the major effect of striatal dopamine deficiency?
hypokinesia -> the paucity of movement
What behavior is associated with low levels of 5-HIAA in the CSF?
impulsive violence
Where are neuropeptides synthesized?
in the cell body and then transported to the nerve terminal
What do tricyclic antidepressants do? How effective are they?
inhibit NET and SERT with very weak effect on DAT; clinical benefits of drugs take several weeks of continued use to become evident, through inhibition occurs very rapidly
What does the drug lithium do?
inhibits the phosphatase that removes the phosphate in position 1 of the inositol backbone
Not many drugs act on signal transduction. What is one that does?
lithium
Where are catecholamines synthesized?
locally synthesized at the nerve terminal
What enzymes catabolize catacholamines?
monoamine oxidase (MAO) and COMT
What are the four different neurotrophins?
nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4
What are neurotrophic factors?
peptides that support growth, differentiation, and survival of neurons
What types of receptors mediate the synaptic actions of GABA?
postsynaptic GABA(A) receptors (ligand-gated channels), GABA(B) receptors (G protein-coupled), and presynaptic GABA(B) receptors
What are the possible fates of catecholamines that enter the synapse?
postsynaptic receptor activation, postsynaptic autoreceptor activation, transporter-mediated reuptake into presynaptic terminal, enzymatic degradation, passive diffusion
Where are AMPA and NMDA receptors localized? What about metabotropic glutamate receptors?
postsynaptic spine; postsynaptic spine and presynaptic terminal
Where is epinephrine produced? What does it act as?
produced in the adrenal medulla; acts as a circulating hormone
What does nerve growth factor do? What could it possibly be used to treat?
promotes the survival of cholinergic neurons in the septal nuclei of the basal forebrain; Alzheimer disease
What enzyme removes the phosphate group from a protein?
protein phosphatase
How are monoamines, including DA, removed from the synapse?
reuptake
How is GABA removed from the synapse?
reuptake and uptake into glia cells and postsynaptic neurons
How is function activity of synaptically released catecholamines primarily terminated?
reuptake into presynaptic terminal via plasma membrane transporters, which can operate bidirectionally
How is functional activity of serotonin primarily terminated?
reuptake into the nerve terminal
What terminates the synaptic action of glutamate?
reuptake, mostly by glial transporters
Every protein can undergo phosphorylation, but which two amino acids can be phosphorylated?
serine, threonine
What receptors does Prozac block?
serotonin
Active zone
site of neurotransmitter release
Is protein phosphorylation more directly related to slow synaptic transmission or fast synaptic transmission?
slow synaptic transmission
How are the synaptic actions of ACh terminated?
terminated by the enzyme acetylcholinesterase (AChE) which hydrolyzes ACh into choline and acetic acid
What causes Parkinson's disease?
the death of dopamine cells in the substantia nigra pars compacta and the resulting depletion of dopamine in the striatum; there is also an increase of activity in GABAergic projection neurons which receive cholinergic inputs from local interneurons
What amino acid is serotonin synthesized from? What is the rate-limiting enzyme in serotonin synthesis?
tryptophan; tryptophan hydroxylase (TPH)
Asymmetrical synapse
typically excitatory synapses that have glutamate receptors
Symmetrical synapse
typically inhibitory synapses that have glycine or GABA receptors
How is glutamate removed from the synapse?
uptake into glia cells and postsynaptic neurons
What type of transporters are responsible for reuptake?
vesicular transporters