Flashcards in 2 - ACh, glutamate, GABA and glycine Deck (75):
Acetylcholine is an ester of ____ and ____
Acetylcholine is an ester of acetic acid and choline
What is the formula for the synthesis of acetylcholine?
Choline + acetyl CoA Acetylcholine + coenzyme A
Where is the highest density of cholinergic interneurons found?
Caudate-putamen (part of basal ganglia), modulates movement control
ACh neurons in the brain stem are mostly ____
what are three functions of basal forebrain cholinergic neurons?
Which divisions of the PNS are cholinergic neurons involved in?
- Sympathetic (short preganglionic neuron)
- Parasympathetic (long preganglionic neuron)
The sympathetic nervous system serviced by what two type of cholinergic tissue receptors?
The parasympathetic nervous system serviced by what type of cholinergic tissue receptor?
Somatic neurons of the PNS are serviced by what type of cholinergic tissue receptor?
What is ChAT?
Choline acetyl transferase,
The role of choline acetyltransferase is to join Acetyl-CoA to choline
Synthesized within the nerve terminal
What is CHT1?
Choline transporter 1
Transports choline into presynaptic terminal (reuptake) where it can be used to synthesize ACh again. Acetyl CoA is not reuptaken in this fashion as it is degraded into acetate by AChE
What is VAChT?
Vesicular acetylcholine transporter
Loads ACh into vesicles
What is AChE?
Responsible for breaking acetylcholine into choline and acetate in the synapse
Which ACh receptor is fast and which is slow?
Muscarinic: Slow (metabotropic)
Nicotinic: Fast (ionotropic)
What subtype of muscarinic receptors are there and what are the associated G proteins?
M1, M3 and M5: Gq
M2, M4: Gi coupled
Are muscarinic/nicotinic receptors excitatory or inhibitory?
What type of muscles are nicotinic and muscarinic receptors found in?
Muscarinic: Smooth muscles
Nicotinic: Striated muscle
True or false? Nicotinic receptors are heteromeric?
False. Mostly heteromeric, but also homomeric (α7 subunits, present in CNS and characterized by high Ca permeability).
How many subunits do nicotinic receptors have? What type of subunits are found in the most common heteromeric nicotinic receptor?
9 different α subunits and 3 different β subunits
Name three subtypes of the nicotinic receptor subunits and their function
α7 - Most common
α5 - Controls nicotine intake
α7 - Working memory and attention in hippocampus
β2 - Sudden infant death syndrome (SIDS)
What is the distribution of muscarinic and nicotinic receptors in the brain?
More muscarinic receptors in newer parts of the brain (eg. forebrain) and nicotinic receptors more common in phylogenetically older areas
What three muscarinic receptors are coupled with the Gq protein?
M1, M3 and M5
stimulation activates protein kinase C by activation of phospholipase C (PLC) and inositol triphosphate (IP3)
What two muscarinic receptors are coupled with the Gi protein?
M2 and M4
Stimulation inhibits adenylyl cyclase
Stimulation of each muscarinic receptor subtype induces the transactivation of what?
Epidermal growth factor receptor (EGRF)
What is rapsyn?
A scaffolding protein responsible for clustering of cholinergic nicotinic receptors at neuromuscular junctions.
Necessary for muscle function, lack of rapsyn causes weakness, breathing difficulty and death within hours of birth (in mice)
What are acetylcholinesterase inhibitors?
- Treatment of choice for alzheimers
- Irreversible inhibitors used as chemical weapons and pesticides
What are nicotinic agonists?
- Treatment for Alzheimers, ADHD and schizophrenia (in trials)
- Can be used as insecticide (killed the bees?)
What is a use for nicotinic antagonists?
Short acting muscle relaxants. Centrally acting antagonists are being considered to be used in treating drug addiction.
What are two uses for muscarinic agonists?
- To reduce intraocular pressure when applied to the eye (to treat glaucoma)
- Applied in certain cases of smooth muscle atonia (muscle weakness)
What are three uses for muscarinic antagonists?
- Preventing motion sickness
- Centrally acting muscarinic antagonists are useful for treating Parkinson's disease
- Atropine is useful to dilate pupils
What is the most abundant neurotransmitter in the nervous system?
Why are there relatively few clinically drugs affecting the glutamatergic system?
Because of the great abundance of glutamatergic synapses in the brain
What enzyme converts glutamate to GABA?
glutamate decarboxylase (GAD)
What are the three types of ionotropic glutamate receptors?
Which of the three ionotropic glutamate receptors has endogenous ligands besides glutamate? How does this affect its activation?
NMDA receptors can also bind with glycine
The NMDA receptor is only activated in the presence of both glutamate and glycine
Abnormal AMPA receptors can cause what three problems?
- Neurodevelopment disorders
- Neurodegenerative disorders (eg. ALS, Alzheimers)
- Glioblastoma tumors
Abnormal kainate receptors can cause what three symptoms?
- Neuropathic pain
- Fear memory
What is the general structure of an ionotropic glutamate receptor? (4)
- Agonist binding site (extracellular)
- Three transmembrane domains
- Cytoplasm facing membrane loop forming the channel pore
- Carboxy terminal (intracellular) is important for modifications such as phosphorylation or interactions with cytoplasmic proteins
What is associated with an overabundance of glutamate?
Excitotoxicity of neurons, involving the activation of NMDA receptors. Prolonged elevation of intracellular calcium leads to mitochondrial damage and apoptosis
What three NMDA receptor antagonists are used in therapy? Why are these often used as recreational drugs?
- Ketamines (anasesthesia)
- Dextromethorphan (cough suppressant)
- Dizocilpine (MK-801) (stroke and Alzheimers's prevention)
Psychotomimetic effects of NMDA antagonists make these popular recreational drugs
Metabotropic glutamate receptors are divided into three groups (group I, group II and group III). Name the members of each group and their G protein
Group I (Gq)
Group II (Gi/Go)
Group III (Gi/Go)
What is the venus flytrap (VFT) of mGlu metabotropic glutamate receptors?
The extracellular cleft of mGlu receptors that closes when bound to an agonist
These G protein-coupled receptors are (uniquely) dimers, a disulfide bonds links the two VFT parts
Where is the mGluR1 receptor found?
- Purkinje cells in cerebellum (eye movement)
- Olfactory bulb
- Hippocampus (spatial memory)
- Glial cells
Where is the mGluR2 receptor found?
- Golgi cells in cerebellum
- Dentate granule neurons of the hippocampus (inhibition of Ca2+ channels)
Where is the mGluR3 receptor found?
- Thalamus and astrocytes
What is the function of mGluR4(7)(8) receptors?
- Presynaptic control of GLU and GABA release
What does knockout of the mGluR7 gene do in mice?
Leads to rapid development of general epilepsy and death
Where is the mGluR5 receptor found?
- Sensory neurons
- Retina amacrine cells
Where is the mGluR6 receptor found?
- Postsynaptic on bipolar cells in the retina
What does knockout of the mGluR8 gene do in mice?
Results in anxiety and weight gain
What is the full name for GABA?
How is the majority of GABA synthesized?
Synthesized from glutamate by glutamate decarboxylase (GAD)
What is the most important inhibitory neurotransmitter in the mammalian brain?
GABA is present in 20% of neurons, but also in non-neuronal tissues, especially in the ___?
What are the two GABA receptors? Which is ionotropic/metabotropic?
- GABAa receptor (ionotropic, postsynaptic)
- GABAb receptor (pre/postsynaptic, metabotropic)
What is the structure of GABAa receptors?
Cys-loop, pentameric membrane proteins that operate as GABA-gated chloride channels
GABAa-ρ receptors are found where and have what characteristic?
Found in the retina and are insensitive to GABAa antagonists bicuculine, barbiturates, benzodiazepines and steroids
What is the structure of the GABAb receptor?
- Comprised of two subunits, GABAb1 and GABAb2, inserted into the plasma membrane and coupled intracellularly
Which subunit of GABAb receptor contains the GABA binding domain in its extracellular N-terminal chain?
What does GABAb2 do?
Does not bind GABA, but modulates within the transmembrane region.
When stimulated, what does the GABAb receptor do?
Inhibits cAMP, increases potassium conductance and decreases calcium conductance.
What is benzodiazepines action on GABAa receptors?
They act to increase affinity for GABA, they have no action in the absence of GABA.
Knockout of the α1 and β2 subunits (most abundant subunits) of GABAa show what in mice?
The mice survive, showing there must be some compensatory mechanism
Mice lacking one (heterozygous) or both γ2 alleles show what?
Both alleles: death due to lack of receptor clustering
Heterozygous: model for anxiety disorder
What do agonists of GABAa do?
Act as anaesthetics and treatments for insomnia
Baclofen, the only GABAb receptor agonist, is used for what?
Muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis
Broadly, what is the function of glycine?
Mediator of synaptic inhibition, mostly in brain stem, spinal cord and retina
Vesicular transport of glycine is not mediated by glycine transporters. What transporters do this?
What does Tetanus disease do?
Presynaptic block of glycine release
Which neurotransmitter was found in space?
Subunits of glycine receptors assemble into what sort of complex?
Pentameric channels, thought to form rosette like arrangements surrounding a central ion pore.
What are P and K on glycine receptors?
Positions of amino acid exchanges associated with the human neurological disorder hyperekplexia (exaggerated surprise) (acute startle response)
In mice, the complete loss of the α1 subunit of glycine receptors is lethal. It is tolerated in humans. What does this suggest?
The loss of glycine receptors is effectively compensated in humans or subunit regulation substantially differs among these species.
True or false? Glycine receptors have no pharmaceuticals that target them.