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Chapter 7: Aceytlcholine - Coggle Diagram

- - - - acetylcholine +coenzymeA
  - - - Release
        
        affected by various animal and becterial TOXINS
        
        Black widow spider venom (LTX) --> MASSIVE RELEASE of ACh in the PNS
        
        produces muscle pain, tremors, nausea, vomiting, increased salivation, sweating
        
        even though sweating is synpathetic, there's ACh in postganglionic fibers in sweat glands
        
        2 Mechanisms of action
        
        a-LTX interacts with neurexins on neuronal membrane --> creates pore to allow Ca++ influx
        
        a-LTX stimulates latrophilin
        
        linked to Gq
        
        1 more item...
        
        Botulinum toxin: bacterial toxin BLOCKS ACh RELEASE at NMJ
        
        Cleaves different snare proteins: lack of vesicle fusion in presynaptic membrane, no NT release into synapse)
        
        No ACh in NMJ, muscles can't contract --> MUSCLE PARALYSIS
        
        Medical uses
        
        botox into a wrinkle (hypercontracted muscle) --> alleviates this state
        
        Tourette's: involuntary muscle contractions
        
        skull for migrains
        
        hyperhydrosis: reduce sweating by blocking ACh
  - - - AChE breaks ACh down to choline and acetic acid
        
        on postsynaptic cell: breaks down ACh after release into cleft
        
        in presynaptic cell: can metabolize excess ACh that has been synthesized
      - most choline in cleft is TAKEN BACK into nerve terminal by a choline transporter
        
        if you BLOCK choline transporter, prevent reuptake --> reduce precursor --> reduced ACh release
      - AChE at NMJ
        
        muscle cells release AChE into the cleft --> immobilized until ACh is released
        
        ACh is broken down rapidly so muscle can RELAX before the next contraction
      - Anticholinesterases: AChE Inhibitors (inhibit breakdown of ACh)
        
        Irreversible inhibitors
        
        weak versions: insecticides
        
        very toxic varieties: nerve gases, sarin, soma, VX
        
        ACh accumulation and overstimulation of cholinergic synapses throughout both CNS and PNS leads to MUSCLE PARALYSIS (DEPOLARIZATION BLOCK) and death by asphyxiation
        
        Reversible inhibitors: drug temporarily inhibits AChE --> increase in ACh --> unbinds to AChE
        
        Medical use: Myasthenia Gravis
        
        body makes antibodies against ACh Receptors at NMJ --> muscle weakness
        
        Treat with reversible inhibitors that do not cross BBB (enhanced levels of ACh at the synapse to act on receptors that are functional)
        
        Gulf War Syndrome: caused by chronic REVERSIBLE anticholinesterase
        
        PB tablets given to soldiers who might be exposed to Sarin (IRREVERSIBLE)
        
        Sarin wouldn't be able to bind because AChE is already bounded by PB
        
        HOWEVER, PB showed significant penetration across the BBB (stressful conditions will lead to PB crossing BBB)
- - - - regulation of movement depends on the BALANCE between ACh and DA
        
        Anticholinergics (muscarinic receptor antagonists) for Parkinsons: block ACh signaling in striatum, restore balance
    - - damage to cholinergic system --> contributes to COGNITIVE FACTORS in Alzheimer's
        
        increase ACh levels to treat Alzheimer's (large doses are not effective)
        
        better alternative: central cholinesterase inhibitor gets into brain, crosses BBB
    - - some axons from these cells have EXCITATORY influence on MIDRBRAIN DA neuron firing
        
        project to brainstem and thalamic areas
        
        important for behavioral arousal, sensory processing, initiation of REM sleep
  - - - highly concentrated at the NMJ, also on ganglionic neurons in ANS and some brain regions
      - mediate fast excitatory responses
      - 3 functional states
        
        open: receptor comes into contact w/ ACh --> conformational change --> allow ions to flow through
        
        desensitization: continuous agonist exposure --> channel remains CLOSED, will SPONTANEOUSLY re-sensitize
        
        Chronically opened state: even w/ chronic agonists, not all receptors desensitize
        
        chronic influx of positive ions
        
        persistent depolarization
        
        depolarization block: resting potential of the membrane is lost, cell can't be excited until agonist is removed and the membrane repolarized
      - Clinical applications
        
        Varenicline: partial agonist at high-affinity alpha-4-beta-2 nicotinic receptors expressed in the VTA
        
        provide enough relief to prevent patient from going back to nicotine
        
        a7 agonists to improve cognitive performance
        
        a7 subunit highly expressed in regions implicated in cognition and memory
        
        stimulation of a7 receptors IMPROVES attention/cognitive performance
        
        significant reduction of a7 in the brain (hippocampus) has been reported in Alzheimer's and schizophrenia
    - - Widely distributed
        
        major receptor of postganglionic ACh in parasympathetic NS
      - 5 types: M1-M5, operate via 2nd messengers
        
        M1, M3, M5: activate PLC (Gq)
        
        M5: hippocampus, hypothalamus, midbrain DA (VTA)
        
        leads to ENHANCED DA release in nucleus accumbens (reward system)
        
        M5 receptors in drug abuse: M5KO mice exhibit deficits in morphine and cocaine reward
        
        M5 receptor antagonists for drug dependence
        
        KO mice still show analgesia (M5 receptors only affects reward pathway not analgesic pathway)
        
        M2, M4: inhibit AC (Gi)
        
        opens K+ channels
      - Muscarinic receptor agonists: parasympatho-mimetic agents (PARASYMPATHETIC ACTIVATION)