2. Ch 7 Aceytlcholines Flashcards
how was ACh identified
first NT identified by Loewi in his heart chambers experiment “vagusstoff”
ACh Synthesis
Choline + Acetyl CoA = Acetylcholine + Coenzyme A
using bidirectional enzyme Choline acetyl-transferase (ChAT)
Where ChAT found, how is ACh rate controlled
ChAT only found in ACh neurons (specific marker of cholinergic neurons)
Rate of ACh synthesis controlled by availability of precursors and rate of cell firing
How does ACh move into vesicles
via vesicular ACh transporter (VAChT)
VAChT blocked by a vesamicol = decreases vesicular ACh = less ACh released
How does Black widow venom affect ACh release (two mechanisms)
venom called alpha LTX, causes masisve release of ACh in PNS causing tremors/sweat/muscle pain
1) Alpha LTX interacts with neurexins on membrane, inserts LTX into membrane causing Ca2+ influx = release ACh
2) Alpha LTX stimulated latrophilin, linked to Gq = PLC activate = release Ca2+ from stores = release ACh
How does Botulinum toxin interact with ACh
blocks release at NMJ (most potent toxin)
causes muscle paralysis by cleaving vesicle snare proteins = no release
used in botox/Tourette’s syndrome/hyperhydrosis
How does AChE work
acetylcholinesterase controls levels of ACh
breaks it down into choline/acetic acid
presynaptically - metabolizes excess ACh
postsyn - on membrane, breaks down ACh in cleft
G4 version of AChE
Cholinergic neurons and postsyn that recieve ACh input make G4 AChE version
bound to membrane by tail
A12 version of AChE
at NMJ, muscle cells make A12
has a collagen tail to anchor it to extracellular matrix
breaks down ACh very rapidly so muscle can relax quickly
Why no reuptake of ACh
No ACh transporters
metabolized in synapse and choline is reuptaken
50% of choline is recycled, important in maintaining ACh
irreversible AChE inhibitors
insecticides and nerve gases
causes ACh accumulation throughout CNS/PNS
muscle paralysis, death by asphyxiation since receptros get desensitized thru constant stimulation
myasthenia gravis
autoimmune disorder attacks ACh receptors at NMJ
leads to muscle weakness
treat with reversible AChE inhibitors that don’t cross BBB
these AChE inhibitors allow ACh to be as present as possible to bind to receptors
Gulf War Syndrome story
troops receieved PB tablets (reversible AChE inhibitor) to prevent nerve gas toxicity but it could cross BBB, and with stress caused inhibition of AChE
Excess ACh in brain caused many symptoms long term
where is ACh found
NMJ, CNS, ANS
very ubiquitous
where nAChR/mAChR
nAChR - autonomic ganglia in para and sympathetic
mAChR - post gang target organs, parasympathetic except sweat glands
Cholinergic soma locations in CNS
striatum, basal forebrain cholinergic system, dorsolateral pons
Cholinergic somas in Striatum and parkinsons loop
interneurons
regulate movement depends on balance of ACh and DA
muscarinic antagonists treat parkinsons
Parkinsons loop = SN uses DA to inhibit Striatum, which uses ACh. Parkinsons means SN dies, so too much ACh, inhibit them to treat tremors
Cholinergic in basal forebrain cholinergic system
origin of dense cholin. innervation in cortex/hippo/limbic
damage contributes to cog factors of alzheimer’s
can’t treat with doses of ACh, treat with AChE inhibitors
Cholinergic in dorsolateral pons
excite midbrain DA
project to brainstem/thal
roles in arousal/sensory process/REM sleep
2 families of cholinergic receptors
Nicotinic - ionotropic and agonist nicotine
Muscarinic - metabotropic and agonist muscarine
Organization of Nicotinic Receptors
concentrated at NMJ and autonomic ganglia in ANS
mediate fast excitatory responses
made in Pentamers - five subunits, diff combinations of those 5 (10 different alpha/4beta)
Functional States of Nicotinic Receptors
Open, Closed, or Desensitized
Desensitized = after continuous agonist, channel remains closed even if bound agonist, needs time to resensitize
Depolarization block in receptors
sometimes receptors don’t desensitize with continuous agonist
produces a persistent depolarization of membrane and depol block occurs = resting potential lost
can’t be excited again til agonist removed and can repol.
SSuccinylcholine is a muscle relaxant used in surgery that resists AChE and causes depol block, no more APs
nAChR clinical applications
Varenicline is a partial agonist of Alpha4Beta2 nAChRs in VTA, allows less efficacy of nicotine, stop smoking
Alpha7 agonists might improve cog performance, Alpha7 in cog/memory regions, stimulation improves att’n/performance. Alzheimers/Schizo have less Alpha7 in hippo
Muscarinic Receptor organization
widely distirbuted, more common than nAChR
postganglionic in parasympathetic
5 types, M1-5
Operate via 2nd messenger
M1,3,5 = activate PLC Gq
M2,4 = inhibit AC Gi, also open K channels, effect depends on cell
M5 receptors
in hippo/hypothal/midbrain DA
leads to enhanced DA release in nucleus accumbens
M5 and drug abuse
M5 KO mice = deficit in morphine/cocaine reward (cond. place pref)
still show morphine analgesia
so only affects reward path, not analgesic
maybe M5 antagonists treat addiction?
M5 negative allosteric modulating and ethanol
neg. allos. modulator = reduce effect of ACh, non comp antagonist
it reduces voluntary ethanol consumption, but not sugar intake (control for general rewarding stimulus)
Muscarinic receptor agonists
parasympatho-mimetic agents
rest and digest
Muscarinic receptor Antagonists
parasympatholytic agents
fight or flight
“anticholinergic effects” - dry mouth, retain urine
many psychitric drugs are antagonists of muscarinic PNS
Schizophrenia and Muscarinic Receptors
KarXT is muscarinic agonist and antagonist
Agonist crosses BBB, preferentially stimulates CNS muscarinic (reduced receptors in schizo)
Antagonist inhibits the agonist stim’s in PNS (no net effect in PNS)
Doesn’t rely on DA/5HT paths
