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  <head>
    <title>002-02 Electrochemical gradients, synaptic computation, and receptor adaptation</title>
    <ownerName>Integrated Medical Foundations</ownerName>
  </head>
  <body>
    <outline text="Gradients, synaptic computation, receptor adaptation">
      <outline text="Equilibrium potentials and potassium">
        <outline text="Voltage from gradients plus selective conductance"/>
        <outline text="Equilibrium: electrical and concentration forces balance"/>
        <outline text="Resting neuron mostly permeable to potassium">
          <outline text="Rest lies nearer potassium than sodium equilibrium"/>
          <outline text="Chloride and electrogenic transport contribute"/>
        </outline>
        <outline text="Extracellular potassium alters the efflux gradient">
          <outline text="Hyperkalaemia: resting potential less negative"/>
          <outline text="Sustained depolarisation inactivates sodium channels"/>
          <outline text="Hypokalaemia: harder excitation, altered repolarisation"/>
        </outline>
        <outline text="Effect depends on speed, size, acid-base, medicines"/>
      </outline>
      <outline text="Pump and driving force">
        <outline text="Pump maintains gradients, not each action potential">
          <outline text="Brief activity runs on existing gradients"/>
        </outline>
        <outline text="Energy failure: delayed but catastrophic">
          <outline text="Gradients decay, cells swell, calcium fails"/>
        </outline>
        <outline text="Current depends on conductance and driving force"/>
        <outline text="Direction set by voltage versus equilibrium potential">
          <outline text="Chloride opening inhibits mature neurons"/>
          <outline text="Altered chloride gradients change the effect"/>
        </outline>
      </outline>
      <outline text="Action-potential diversity">
        <outline text="Channel types, timing, expression differ by tissue"/>
        <outline text="Peripheral axon: rapid sodium-dependent spike"/>
        <outline text="Ventricular muscle: calcium-supported plateau">
          <outline text="Long refractory period prevents tetanic activation"/>
        </outline>
        <outline text="Pacemaker cells depolarise spontaneously in diastole"/>
        <outline text="Shared regenerative opening, adapted waveform"/>
        <outline text="Absolute refractory: sodium channels inactivated"/>
        <outline text="Relative refractory: stronger stimulus required">
          <outline text="Limits frequency, separates impulses, shapes re-entry"/>
        </outline>
      </outline>
      <outline text="Conduction failure and temperature">
        <outline text="Demyelination leaks current before the next node"/>
        <outline text="Compression impairs membrane and blood flow"/>
        <outline text="Ischaemia reduces energy supply"/>
        <outline text="Local anaesthetics: use-dependent sodium block">
          <outline text="Small, fast-firing axons often affected first"/>
        </outline>
        <outline text="Cooling slows nerves, prolongs cardiac intervals"/>
        <outline text="Fever may expose channel disorders or seizures"/>
        <outline text="Excitability is protein chemistry, not abstract circuitry"/>
      </outline>
      <outline text="Synaptic control and integration">
        <outline text="Presynaptic: calcium, vesicles, autoreceptors">
          <outline text="Axo-axonic inhibition limits release"/>
        </outline>
        <outline text="Postsynaptic: receptor number, type, location"/>
        <outline text="Uptake and enzymes set duration">
          <outline text="Drugs alter signalling without mimicking transmitter"/>
        </outline>
        <outline text="Spatial and temporal summation">
          <outline text="Distal excitation weakens with distance"/>
          <outline text="Perisomatic inhibition gates the initial segment"/>
        </outline>
      </outline>
      <outline text="Forms of inhibition and plasticity">
        <outline text="Hyperpolarising inhibition moves away from threshold"/>
        <outline text="Shunting inhibition dissipates excitatory current"/>
        <outline text="Disinhibition activates without direct excitation">
          <outline text="Select, sharpen contrast, time, prevent runaway"/>
        </outline>
        <outline text="Short-term facilitation from residual calcium"/>
        <outline text="Short-term depression from vesicle depletion"/>
        <outline text="Long-term change: trafficking, kinases, genes, structure">
          <outline text="Can amplify pain pathways or compulsion"/>
        </outline>
      </outline>
      <outline text="Receptor families and cellular interpretation">
        <outline text="Ligand-gated channels: direct rapid current"/>
        <outline text="G-protein-coupled receptors amplify and regulate"/>
        <outline text="Enzyme-linked receptors: phosphorylation networks"/>
        <outline text="Intracellular receptors regulate genes">
          <outline text="Some produce faster non-genomic effects"/>
        </outline>
        <outline text="Same receptor, different cell, different effect">
          <outline text="Beta receptor: heart rate and force up"/>
          <outline text="Related signalling relaxes some smooth muscle"/>
        </outline>
      </outline>
      <outline text="Agonism, bias, and reserve">
        <outline text="Partial agonist gives a lower maximum">
          <outline text="Can reduce activation beside a full agonist"/>
        </outline>
        <outline text="Inverse agonist lowers constitutive activity"/>
        <outline text="Allosteric modulators bind away from main site"/>
        <outline text="Biased signalling favours particular pathways">
          <outline text="Same named receptor, different drug effects"/>
        </outline>
        <outline text="Receptor reserve preserves maximal response"/>
      </outline>
      <outline text="Adaptation, withdrawal, and testing">
        <outline text="Persistent stimulation desensitises receptors">
          <outline text="Phosphorylation, uncoupling, internalisation"/>
          <outline text="Tolerance has several possible levels"/>
          <outline text="Blind dose escalation adds toxicity"/>
        </outline>
        <outline text="Chronic blockade up-regulates sensitivity">
          <outline text="Abrupt withdrawal causes rebound activity"/>
          <outline text="Plan tapering per current guidance"/>
        </outline>
        <outline text="Endocrine tests are snapshots of dynamic axes">
          <outline text="In-range value may be inappropriate for its controller"/>
          <outline text="Dynamic tests need valid protocol and context"/>
        </outline>
        <outline text="Gradient to channel, cell, network, whole body"/>
      </outline>
    </outline>
  </body>
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