--- module: 002-02 language: en chapter: 2 title: "Membranes, Signalling, and Excitable Cells" module_title: "Electrochemical gradients, synaptic computation, and receptor adaptation" source_sha256: c51851c028b04db042f45358bc5020563e010161c481fb9fa4207261bff64e0e --- # Gradients, synaptic computation, receptor adaptation ## Equilibrium potentials and potassium ### Voltage from gradients plus selective conductance ### Equilibrium: electrical and concentration forces balance ### Resting neuron mostly permeable to potassium #### Rest lies nearer potassium than sodium equilibrium #### Chloride and electrogenic transport contribute ### Extracellular potassium alters the efflux gradient #### Hyperkalaemia: resting potential less negative #### Sustained depolarisation inactivates sodium channels #### Hypokalaemia: harder excitation, altered repolarisation ### Effect depends on speed, size, acid-base, medicines ## Pump and driving force ### Pump maintains gradients, not each action potential #### Brief activity runs on existing gradients ### Energy failure: delayed but catastrophic #### Gradients decay, cells swell, calcium fails ### Current depends on conductance and driving force ### Direction set by voltage versus equilibrium potential #### Chloride opening inhibits mature neurons #### Altered chloride gradients change the effect ## Action-potential diversity ### Channel types, timing, expression differ by tissue ### Peripheral axon: rapid sodium-dependent spike ### Ventricular muscle: calcium-supported plateau #### Long refractory period prevents tetanic activation ### Pacemaker cells depolarise spontaneously in diastole ### Shared regenerative opening, adapted waveform ### Absolute refractory: sodium channels inactivated ### Relative refractory: stronger stimulus required #### Limits frequency, separates impulses, shapes re-entry ## Conduction failure and temperature ### Demyelination leaks current before the next node ### Compression impairs membrane and blood flow ### Ischaemia reduces energy supply ### Local anaesthetics: use-dependent sodium block #### Small, fast-firing axons often affected first ### Cooling slows nerves, prolongs cardiac intervals ### Fever may expose channel disorders or seizures ### Excitability is protein chemistry, not abstract circuitry ## Synaptic control and integration ### Presynaptic: calcium, vesicles, autoreceptors #### Axo-axonic inhibition limits release ### Postsynaptic: receptor number, type, location ### Uptake and enzymes set duration #### Drugs alter signalling without mimicking transmitter ### Spatial and temporal summation #### Distal excitation weakens with distance #### Perisomatic inhibition gates the initial segment ## Forms of inhibition and plasticity ### Hyperpolarising inhibition moves away from threshold ### Shunting inhibition dissipates excitatory current ### Disinhibition activates without direct excitation #### Select, sharpen contrast, time, prevent runaway ### Short-term facilitation from residual calcium ### Short-term depression from vesicle depletion ### Long-term change: trafficking, kinases, genes, structure #### Can amplify pain pathways or compulsion ## Receptor families and cellular interpretation ### Ligand-gated channels: direct rapid current ### G-protein-coupled receptors amplify and regulate ### Enzyme-linked receptors: phosphorylation networks ### Intracellular receptors regulate genes #### Some produce faster non-genomic effects ### Same receptor, different cell, different effect #### Beta receptor: heart rate and force up #### Related signalling relaxes some smooth muscle ## Agonism, bias, and reserve ### Partial agonist gives a lower maximum #### Can reduce activation beside a full agonist ### Inverse agonist lowers constitutive activity ### Allosteric modulators bind away from main site ### Biased signalling favours particular pathways #### Same named receptor, different drug effects ### Receptor reserve preserves maximal response ## Adaptation, withdrawal, and testing ### Persistent stimulation desensitises receptors #### Phosphorylation, uncoupling, internalisation #### Tolerance has several possible levels #### Blind dose escalation adds toxicity ### Chronic blockade up-regulates sensitivity #### Abrupt withdrawal causes rebound activity #### Plan tapering per current guidance ### Endocrine tests are snapshots of dynamic axes #### In-range value may be inappropriate for its controller #### Dynamic tests need valid protocol and context ### Gradient to channel, cell, network, whole body