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Synaptic Transmission (STORAGE = increase speed of transmission of…

- - - - GASES = lipophilic molecules with intracellular receptor
        
        NO
        
        CO
      - PURINES
        
        ATP --> Puringengic Receptors
      - LIPIDS = cannabinoids that dissolve in membranes + discovered from exogenous molecules
        
        ANANDAMIDE = endogenous canabinoid 'bliss' molecule, approved for Intractable Epilespsy + MS treatment from Summer 2018
    - - BIOLOGICAL AMINES
        
        NOREPINEPHRINE
        
        Metabotropic Adrenergic Receptor
        
        A1 = Phospholipase C --> IP3 + DAG
        
        A2 = Inhibit Adenylate Cyclase --> Lower cAMP
        
        B1-3 = Activate Adenylate Kinase --> Increase cAMP
        
        DOPAMINE
        
        Excitatory or Inhibitory dependent on receptor
        
        SEROTONIN
      - AA
        
        E
        
        Mostly Excitatory
        
        G
        
        Most Inhibitory Cl- Channels
        
        GABA
        
        Mostly Inhibitory Cl- Channels
    - - SUBSTANCE P = pain fibre neurotransmitter
      - OPOIDS = analgesics discovered from exogenous morphine effects
        
        Endorphins
        
        Enkaphalins
  - - - Mostly created from an above threshold Na-induced initial depolarisation
    - - Initial Hyperpolarisation due to opening Cl- entering or K leaving
    - - IONOTROPIC = single binding step with faster transmitter limited to hyper/depolarisation
        
        Coformational change to open central pore CGIC Complexes
        
        Neurotransmitter bind to ECF
      - METABOTROPIC = 7 transmembrane serpentine proteins for sensory + endocrine systems
        
        Lipid anchors link G proteins
        
        Move within membrane to interact with effector molecules
        
        cAMP = common metabolite/intracellular signalling molecule
        
        Kinase Activation
        
        Ion Channel Ease of Opening
        
        Trigger gene expression to remodel synapses
        
        Multiple Binding Steps = Slower transmission
  - - - Biogenics = NT
      - AA = NT + G
- - - - Pentameric complex from 17 different types = altering ion specificity/permeability
      - NICOTINE = AGONIST
    - - 5 Subtypes with MUSCARINE AGONIST
        
        M2 + M4 = inhibit ADENYLATE CYCLASE + coupled to K/Ca channels
        
        M1 + M3 + M5 = activate PHOSPHOLIPASE C to increase Intracellular Ca + activate kinase
  - - - CHOLINE --> recycled in nerve terminal
      - ACETIC ACID --> diffusion from cleft
      - NOVITCHOK = inhibitor of acetylcholinesterase --> respiratory failure
    - - Membrane Phosphodiocholine --> CHOLINE
      - Choline Transporter = Move from PM --> Terminal
      - Mitchochondrial Glucose Metabolism = Pyruvate --> ACETYL-COA
- - - - NEUROMUSCULAR JUNCTION = cholinergic synapse
        
        Motor Unit = 1 somatic motor neuron + all muscle fibres it innervates
        
        Avoids faitgue by motor unit alteration
        
        Large Motor Units in Leg
        
        Fine Motor Control = Fingers
        
        Motor-End Plate = post-junctional folds on muscle membrane for receptor clustering
        
        Pentameric Ionotropic Receptor = alpha --> e
        
        Each receptor = 2 alpha subunits to bind 2 external AcH to open on channel
      - 1 neuron with cell body in ventral horn, uninterrupted myelinated motor axons and branched terminals to innervate multiples
      - Excitatory Potentionals from AcH --> nAcHR
      - Spinal Cord Inhibitory Interneurons = reduce motor neuron excitation
    - - NEUROEFFECTOR JUNCTION = mAChR for smooth muscle
        
        Axons ending in Varisocities = series of terminals containing synaptic vesicles extending over muscle fibre bed
        
        SINGLE-UNIT SMOOTH MUSCLE = signal spread from one muscle fibre
        
        MUTLI-UNIT SMOOTH MUSCLE = all see neurotransmitter directly
      - SYMPATHETIC FIBRES
        
        Post-Ganglionic = carter potential to effector organ
        
        Sympathetic chain = chain of interconnected ganglion
        
        Pre-Ganglionic = Short axon to sympathetic chain from cell bodies in thoracic + upper lumbar regions of spinal cord (nuclei in Lateral Horn)
        
        ACh --> nAChR
        
        Noreadrenaline --> Adrenergic Receptor
      - PARASYMPATHETIC FIBRES
        
        Pre-Ganglionic = Long axons extending from sacral region of spinal cord or brain stem
        
        Ganglia situated close to organ
        
        Post-Ganglionic = Short axons extending from ganglia to effector
        
        ACh --> mAChR
        
        ACh --> nAChR
- - - - SYMPTOMS
        
        Long-Lasting Alterations in Mood
        
        Inability to Sleep
        
        Apetite Changes
        
        Work/study/personal relationships
      - LIMBIC SYSTEM
        
        MAJOR DEPRESSION = down regulation of biogenic amine transmitters
        
        MANIC-DEPRESSION = over regulation of cholinergic synapses
      - CAUSES
        
        GENETIC = Endogenous Depression
        
        Tyrosine Hydroxylase Mutations = failure to synthesise dopamine or Noradrenaline from phylalaine/tyrosine pathway
        
        Some evidence for loss of glutamatergic neuronal loss in hippocampus + prefrontal cortex
        
        MONOAMINE THEORY = functional deficit/excess monoamine transmitters (NaD + 5-HT)
        
        Imaging + Neurochemistry have shown associations with
        
        Pre-frontal cortex
        
        Amygdala
        
        Hippocampus
        
        STRESS = Exogenous/Reactive Depression
        
        Long Term Stress = over activity of noradrenergic transmission = down reg. of other systems in compensation = impairing transmission
        
        Hypothalamic Cells --> Corticotrophin-Releasing Hormone --> Stimulate Pituitary Cells --> Adrenocorticotrophic Hormone→ High Coritsol --> Linked to progression of depressive symptoms
      - TREATMENT
        
        SSRI = Selective Serotonin Re-Uptake Inhibitors - prolong [Serotonin]
        
        SEROTONIN SYNDROME - excess stimulation of 5HT(2-4)
        
        Tremors
        
        Prolonged QT Interval
        
        Hyperthermia
        
        SNRI = Serotonin/Norepinephrine Re-Uptake Inhibitor - Prolong [Serotonin] + [Norepinephrine]
        
        Duloxetine
        
        Monoamines together promote neurogenesis
        
        MOA = Monoamine Oxidase Inhibitor - maintain [Monoamines]
        
        MOA-a = relative substrate specificity for Dopamine
        
        MOA-b = relative substrate specificity for Seretonin + norepinephrine
        
        TCA = Tricyclic Antidepressants - complete for amine transporter binging site to block norepinephrine uptake
        
        Muscarinic AcHR Side Effects
        
        Postural Hypotension from enhances noreadrenergic transmission in medullary vasomotor centre
        
        Confusion
        
        Sedation
        
        Amitriptyline (now used for analgesic)
    - - END-PLATE ACETYLCHOLINESTERASE DEFICIENCY = overstimulation of skeletal muscle fibres via constant flow of cations into cell
      - POST-SYNAPTIC
        
        MYASTHENIA GRAVIS
        
        Auto-Ab against specific subunits of nAChR resulting in net loss of functional receptors
        
        Blocking transmistter binding
        
        Increasing rate of receptor degradation
        
        Inflammation causing postsynaptic membrane destruction + cell lysis
        
        Most common myasthenia disorder (15-20/100,000) dye to neonatal form from active MG maternal Ab crossing placenta and creating a initial display of symptoms that is eventually cleared
        
        AcHR DEFICIENCIES
        
        Subunit mutations of pentameric nAChR altering properties of ionotorpic cation channels
        
        Fast Channel Syndrome
        
        Slow Channel Syndrome
      - PRE-SYNAPTIC
        
        LAMBERT-EATON MYASTHENIA
        
        Autoimmune Myasthenic Disorder with Ab against voltage-gated Ca++ channels in presynaptic motor neurone terminal reducing AcH release
        
        Associated with molecular mimicry of Small Cell Lung Carcinoma
        
        CONGENITAL MYASTHENIC SYNDROME WITH EPISODIC APNEA
        
        Insufficiency production of AcH via defective Choline Acetyltransferase