Membrane potential

Diffusion

• Fick's law: net diffusion is proportional to the concentration gradient, membrane area and permeability, and inversely to membrane thickness.
• Through the lipid bilayer, permeability depends mainly on lipid solubility and then on small size. O₂, CO₂, N₂, steroids and anaesthetic gases cross easily; small uncharged molecules (water, urea) cross slowly; ions and glucose hardly at all without a protein.
• In the lungs, CO₂ diffuses about 20 times faster than O₂ because it is far more soluble, despite being heavier.

Carrier-mediated transport

• Facilitated diffusion and co-transport share carrier features: specificity (including stereospecificity: D-glucose is carried, L-glucose is not), saturation with a transport maximum, and competition between similar substrates. They differ in that co-transport can move a solute against its gradient.
• Na⁺/K⁺-ATPase moves 3 Na⁺ out and 2 K⁺ in per ATP. It is electrogenic, keeps cell volume constant and is inhibited by digoxin and ouabain. In hypoxia ATP falls, the pump stops, Na⁺ and water enter and cells swell.
• CFTR is an ATP-gated chloride channel; its failure causes cystic fibrosis.
• Gap junctions (connexons) let ions pass directly between cells, so an action potential spreads from cell to cell in cardiac and visceral smooth muscle.

Ion concentrations and equilibrium potentials

• The Nernst equation gives the potential at which one ion's electrical and chemical forces balance. The Goldman equation combines all ions, each weighted by its permeability, so the membrane potential moves towards the equilibrium potential of whichever ion is most permeable at that moment.

Resting membrane potential

• About −70 mV in neurons and −90 mV in skeletal and cardiac muscle.
• It exists mainly because the resting membrane is most permeable to K⁺ through leak channels; K⁺ diffuses out, leaving negative charge inside, so the potential lies close to the K⁺ equilibrium potential. A small Na⁺ leak makes it slightly less negative.
• The Na⁺/K⁺ pump contributes only a few millivolts directly but maintains the gradients on which the potential depends.
• Hyperkalaemia depolarises the membrane; sustained depolarisation inactivates Na⁺ channels, making cells less excitable (muscle weakness, cardiac arrest). Hypokalaemia hyperpolarises.

Nerve action potential

• Inactivation: each Na⁺ channel has an activation (m) gate and an inactivation (h) gate. Depolarisation opens the m gate quickly and closes the h gate more slowly, so the depolarisation itself inactivates the channel within about a millisecond. The h gate reopens only after repolarisation.
• All-or-none: once threshold is reached, the size is fixed; stimulus strength is coded by firing frequency.
• Absolute refractory period: h gates are closed; no stimulus can fire the cell. Relative refractory period: some Na⁺ channels have recovered and K⁺ conductance is still high, so a stronger stimulus is needed.
• Accommodation: slow depolarisation (for example raised K⁺) inactivates Na⁺ channels without firing.
• Hypocalcaemia increases excitability (tetany, Chvostek and Trousseau signs) because less Ca²⁺ is bound to the outside of Na⁺ channels, lowering the threshold. Hypercalcaemia stabilises membranes.

Conduction

• Velocity rises with diameter and myelination.
• In myelinated axons the myelin insulates the internode; current flows passively and quickly to the next node of Ranvier, where bare membrane is densely packed with voltage-gated Na⁺ channels that regenerate the action potential. This jumping is saltatory conduction. K⁺ channels are concentrated mainly in the juxtaparanodal region under the myelin, not at the node.
• Demyelination (multiple sclerosis, Guillain–Barré) slows or blocks conduction because the exposed internodal membrane has few Na⁺ channels.
• Local anaesthetics block Na⁺ channels from inside; small fibres (B and Aδ, C) are blocked before large ones, so autonomic and pain fibres go first and motor fibres last.
• Toxins: tetrodotoxin (puffer fish) and saxitoxin block Na⁺ channels; tetraethylammonium blocks K⁺ channels.

Graded potentials and synaptic potentials

• Graded (electrotonic) potentials are local, decremental and summate in space and time: generator potentials, end-plate potentials and synaptic potentials.
• EPSP: transmitter (for example glutamate on AMPA receptors) opens non-selective cation channels; Na⁺ influx dominates and depolarises the cell towards threshold.
• IPSP: GABA on GABA-A or glycine receptors opens chloride channels; Cl⁻ influx hyperpolarises the neuron or clamps it near E_Cl. GABA-B receptors work through G proteins that open K⁺ channels (K⁺ efflux). Benzodiazepines increase the frequency of GABA-A channel opening; barbiturates increase the duration.

• Astrocytes do not fire action potentials; they buffer extracellular K⁺, take up glutamate and support neurons.

Cardiac muscle action potential

• In the SA and AV nodes, phase 0 is due to Ca²⁺ influx (slow channels) and phase 4 shows spontaneous depolarisation (funny Na⁺ current), so nodes conduct slowly.

Remember Na⁺ in makes the upstroke; K⁺ out brings it back; Ca²⁺ in holds the cardiac plateau.

Exam trap The resting potential depends mainly on K⁺ permeability, not directly on the pump.

Exam trap Hypocalcaemia makes nerves more excitable, not less.

How FCPS asks about this

• Upstroke of a nerve action potential: Na⁺ influx; repolarisation: K⁺ efflux through voltage-gated channels.
• What closes inactivated Na⁺ channels: the inactivation (h) gate, closed by depolarisation itself.
• Plateau (phase 2) of ventricular action potential: Ca²⁺ influx through L-type channels.
• Node of Ranvier: bare membrane rich in Na⁺ channels allows saltatory conduction.
• EPSP: cation channels letting Na⁺ in; GABA-A hyperpolarisation: chloride influx.
• Similarity between co-transport and facilitated diffusion: both carrier-mediated, specific and saturable.
• Na⁺/K⁺ pump: primary active, 3 Na⁺ out and 2 K⁺ in, blocked by digoxin.