Acetylcholine and glutamate Flashcards
Myasthenia Gravis
Autoimmune disease —> weakness in muscles of the eyes, eyelids and face
- droopy eyelids (in one or both eyes)
- double vision
- difficulty making facial expression
High levels of ACh receptor antibodies in blood
- prescribed cholinestrate inhibitor medication
Choline
Found in high concentrations in the presynaptic terminal
Primarily comes from fat in out diet but can also be produced in small amounts by the liver
choline acetyltransferase
Enzyme required to combine acetly coenzyme A and choline —> acetylcholine
Only present in cholinergic neurons
What junction in ACh found at?
Neuromuscular junction to elicit muscle contractions and act as a neuromodulator in the brain regulating many functions, including memory and sleep
Anatomy of cholinergic pathways
Eight small nuclei in the basal for brain and brainstem for cholinergic nucleus supply the cholinergic innervation in the brain.
The basal forebrain cholinergic nuclei are comprised of the medial septal nucleus, the vertical nucleus of the diagonal band, the horizontal limb of the diagonal band and the nucleus basalis of Meynert, the medial habenula and the parabigeminal nucleus
(See notes)
Synthesis degradation of ACh:
- ACh is synthesised from acetyl CoA and choline
- The newly synthesised transmitter is pumped into vesicles
- The neurotransmitter is released upon the arrival of an action potential
- ACh acts first for a short time on postsynaptic receptors before it is degraded by AChE
- Choline is recycled and pumped back into the presynaptic terminal by the choline transporter
Nicotinic and muscarinic ACh receptors:
Cholinergic receptors are named after selective agonists which mimic the effects of the endogenous ligand (ACh)
Agonist - nicotine, muscarine
Antagonist - curare, atropine
Nomenclature of ACh units and their subunits
-each nicotinic receptor consists of five subunits (α, β, γ, δ, ε)
-There are 10 α and 4 β subunits
- receptors and muscle cells have a different composition than receptors in neurons
- nicotinic receptors are permeable to Na+ and K+ with some subunit combinations also permeable to Ca2+
Myasthesia Gravis testing
- Antibody testing
- Electomyography
- Nestagmine (endrophonium) test
Does inhibition of ACh reverse aging?
Botox in an injectable form of botulinum toxin.
Wrinkles occur when muscles in the face are
chronically activated. Botox
“erases” these wrinkles by paralysing the wrinkle-causing muscles.
Before Treatment: Note the presence of “unsightly” wrinkles above the brow.
After Treatment: The muscles are now paralysed and remain relaxed
Muscarinic ACh receptors - agonists
Carbachol
Arecoline
Pilocarpine
Oxotremorine
Muscarinic ACh receptors - Antagonists
Atropine
Scopolamine
( any excess use of antimuscarinic drugs produces cognitive impairment, and at higher doses delirium, along with tachycardia and other dangerous autonomic symptoms)
Ligands affecting cholinergic transmission
Botulinis and tetanus toxins inhibit ACh release whereas black widow spider toxin stimulates release
Tacrine and physostigmine inhibits AChE
Curare ad mecamylamine are nicotinic antagonists
Varenicline is a partial agonist at nicotinic receptors
Vesamicol inhibits the vesicular acetylcholine transporter
Hemichollinium inhibits the choline transporter
Arecoline is a muscarinic agonist
Atropine and benztropine are muscarinic antagonists
Alzhiemer’s disease
The progressive cognitive decline seen in AD patients is due to neuronal cell death caused by over activation of NMDA receptors and the subsequent pathological increase in intracellular calcium.
Clinical diagnosis: EOAD
Magnetic resonance imagine scan revealed mild generalised cortical atrophy
CT brain imaging revealed additional marked hippocampal atrophy
Symptoms: repetitiveness, memory loss, executive function loss, cognitive decline, difficulty making decisions
Treatment: cholinesterase inhibitor
Autopsy reveal: plaques and tangles with congophilic amyloid angiopathy in addition to prominent Lewy Body pathology noted in the amygdala
Glutamate synthesis
- In the presynaptic terminals of glutamatergic neurons, glutamine (Gln) is converted to glutamate (glut) by the enzyme glutaminase
- Alternatively, glutamate is synthesised by the transmission of aspartate (asp) by transaminase
- After it is released from nerve terminals, glutamate is taken up into glial cells
- Glutamate is converted into glutamine by glutamine synthetase
Glutamate inactivation
- Glutamine is pumped out of the glia by SN1
- Glutamine is taken up by nerve terminals
- Glutamine is converted back to glutamate to replenish the transmitter pool
- Uptake of glutamate into glial cells (and, to a lesser extent, neural) compartments; achieved by the glutamate receptors GLT-1, GLAST and EAAC1
Glutamate receptor types
Described based on different agonists present
Iontropic glutamate receptors (iGluR)
Metabotropic glutamate receptors (mGluR)
Iontropic glutamate receptors
NMDA
AMPA
KAINATE/KAR
(Agonists, largely expressed on the postsynamptic membrane, some are expressed presynaptically e.g KIANATE on mossy fibres in hippocampus)
Metabotropic glutamate receptors
GROUP I (mGlu1, mGlu5)
GROUP II (mGlu2, mGlu3)
GROUP III (mGlu4, mGlu6, mGlu7, mGlu8)
(Divided based on signal transduction based on specific agonists)
Activation by NMDAR, AMPAR (quisqualate) and Kianate Receptors
Kianate —> negative response
Kianate + glycine —> same response as Kianate on its own
Quis —> negative response
Glycine —> no response
NMDA —> no response
NMDA + glycine —> negative response
Glutamate —> negative response
Glutamate + glycine —> elicits greater negative response
Why does glutamate give a response but NMDA doesn’t?
Due to AMPA and KIANATE receptors
Glutamate activates other iGluR
Ketamine
Selective antagonist of NMDA receptors
Used in treatment for depression
Ketamine and Kianate
Ketamine has no effect
Ketamine and quisqualate
Quisqualate is an AMPAR agonist
Ketamine has no effect
Ketamine and NMDA
Ketamine inhibits NMDA
Therefore ketamine is a selective NMDA receptor (reduces spiking) —> why I works as an anaesthetic
Conventional NMDA receptors
Contain 2 GluN1 subunits and 2 GluN2 subunits
Agonists: glutamate and NMDA
Coagonists: glycine and D-serine
Unconventional NDMA receptors
Incorporate GluN3 subunits in addition to either GluN1 or GluN2
Bind to glycine
They are glutamate receptors but activated by glycine
Di-heteromeric NMDARs
Incorporate up to 2 types of different subunits
Not activated by glycine by the same extend as tri-heteromeric receptors
Tri-heteromeric NMDARs
Incorporate 3 types of different subunits
Mg2+ Channels in conventional NMDARs
Have Mg2+ blockers (open channel) —> open in presence of agonists
In presence of magnesium, wont open
Limiting as it prevents calcium entering cell, can lead to apoptosis
Conventional vs. Nonconventional NMDARs
Conventional:
(GluN1/2) —> sensitivity to Mg2+ block
Glu, gly, GluN1, Mg2+
-Ca2+
Nonconventioal:
(GluN1/2/3) —> insensitivity to Mg2+ block
Glu, gly, GluN1, GluN2x, GluN3x
-Ca2+
(GluN1/3) —> insensitivity to Mg2+ block
gly, GluN1,
-Ca
Assembly of NMDARs
GluN3 + GluN1
GluN1 + GluN2/3
Pharmacological targeting NMDARs
epilepsy, stroke, pain, schizophrenia, psychosis, depression, autism, Alzheimer’s
Which compound is a nicotinic receptor agonist?
Varenicline
Which area of the adult brain shows the highest expression of GluN2C subunits?
Hippocampus
