Cell Membrane Potential and Properties

• Most cells have an electrical potential across their membrane

Membrane Properties

• Membranes are mostly impermeable to ions.
• Ions can only cross the membrane through specific proteins like channels, transporters, and pumps.
• A key pump is Na+/K+ ATPase, which pumps Na+ out and K+ into the cell, creating a chemical imbalance where K+ is high inside and Na+ is high outside.
• Leakage channels exist for specific ions.
• The resting membrane potential (RMP) is driven by these factors and underlies action potentials.
• K+ leakage channels allow potassium to slowly diffuse across the membrane, driven by its chemical force.
• K+ ion crosses the membrane, the inside becomes more negative than the outside, which is conventionally called 0mV.
• An electrical force is created that pushes K+ back into the cell.
• The chemical force pushing K+ out and the electrical force pushing it back oppose each other.
• Equilibrium is attained when these forces are equal in magnitude and cancel each other out.

Leakage Channels and Equilibrium (Nernst) Potential

• The cell at rest is very permeable to K+ and slightly permeable to Na+ (leakage channels).
• The K+ chemical gradient pushes K+ out of the cell via leakage channels.
• Since K+ is charged, this sets up electrical imbalance pushing K+ back into the cell.
• If a membrane is only permeable to K+, the electrical force pushing K+ back would equal the chemical force pushing it out, resulting in no net force.
• Nernst equation is used to define the equilibrium potential (E) for K+.
• Nernst equation is useful for making predictions.

Nernst Equation

• Used to calculate equilibrium potential for an ion: Ex = (RT/ZF) * ln([K+]o/[K+]i)
  • T is temperature in Kelvin
  • R is the Gas Constant
  • ZF is the valence of the ion
  • ln is the natural logarithm
• Concentrations of K+ are on the outside/inside of the cell
• The calculated equilibrium potential for K+ is -90mV.
• Equilibrium potential for Na+ = +55mV and for Cl- = -65mV.
• The membrane potential of a healthy cell lies between EK and ENa.

Membrane Potential

• Real membranes are permeable to multiple ions and don't sit at the equilibrium potential for any single ion; they're impacted by all ions.
• The Goldman-Katz equation considers the relative permeability (P) of key ions for calculating actual membrane potential (Vm). Goldmann-Katz equation: Vm = (RT/F) * ln(PK[K+]o + PNa[Na+]o + PCl[Cl-]i) / (PK[K+]i + PNa[Na+]i + PCl[Cl-]o)
• At rest, K+ permeability is highest but this can change under differing conditions.
• Electrical driving force acts on all cations (Na+ and K+)
• Chemical driving force acts on Na+ and K+

Leakage Conductances

• Leakage conductances of the cell act as a buffer to the resting membrane potential.
• Leakage also prevents changes in membrane potential.
• Depolarizing signals diminish with distance because leakage currents dissipate electrical signals in cells.
• To conduct signals over substantial distances, something more is needed.

Action Potential (AP)

• Opening of voltage-gated Na+ (VGSC) channels triggers the rapid, all or none depolarisation, which reliably propagates along axon.
• VGSCs have 3 states: closed at resting membrane potential (RMP), open when triggered by depolarization, and inactivated unable to reopen.
• Stimulus depolarisation opens a small fraction of VGSCs, increasing inward current that further depolarises the membrane, opening even more Na+ channels - Hodgkin Cycle.
• Voltage-gated sodium channels have activation and inactivation gates
• At RMP activation gates are closed and inactivation gates are open
• Activation gates rapidly open as the membrane depolarises to threshold (~ -55mV)
• Inactivation gates also begin to close, but this occurs more slowly
• Sodium rushes down its electrochemical gradient depolarises the membrane and nearby VGSCs which heads towards ENa+
• Inactivation gates swing shut blocking the Na+ current flow and stopping the depolarisation.
• Close packing of VGSCs increases current density and lowers the threshold for an action potential.
• Voltage-gated sodium channels are clustered at the axon hillock trigger zone for AP.
• Voltage-gated K+ channels repolarize the cell.
• Initially the stimulus triggers depolarization and Na+ enters the cell

Voltage-Gated Potassium Channels

• Mostly closed at RMP.
• Open slowly after membrane depolarizes.
• They do not inactivate.
• The higher the depolarization, the larger the fraction of open channels.
• As the cell repolarizes, they slowly close.
• Action potentials result from rapid reversals in relative permeability to Na+ and K+
• Stimulus opens voltage-gated Na+ channels and if the Hodgkin Cycle starts.
• As the membrane further depolarises, Na+ channels begin to inactivate and K+ channels open.
• Shutting off the inward Na+ current increases the outward K+ current and repolarizes the cell.
• Action potentials are all or none, cannot summate, and do not diminish with distance.
• The action potential is always the same size and velocity for a given neuron.
• Neurons signal change by altering the rate of APs, acting as a frequency code.

Refractory Periods

• During the absolute refractory period, voltage-gated Na+ channels are open or inactivated, preventing initiation of another AP and reverberation of APs.
• During the relative refractory period, some voltage-gated K+ channels remain open, hyperpolarising the membrane, while it's possible to drive AP but it would need a bigger depolarising stimulus.

Action Potential Propagation

• Overcoming losses: Action potentials must overcome loss of local circuit current via ion leakage channels, axoplasmic resistance to the flow of depolarizing current and overcoming the large amounts of charge stored on the membrane at rest
• There are 2 propagation strategies, unmyelinated versus myelinated axons
• AP propagation in non-myelinated axons has alternating inactivated and open sodium gates in the membrane
• Large axons offer less resistance to current flow but occupy more space
• Small myelinated axons conduct action potentials as rapidly as large unmyelinated axons.

Myelination

• Myelin forms around a small segment of one axon
• Myelination is from peripheral nervous system
• Myelin accelerates AP propagation acting as an insulator
• There are Sections of unmyelinated axon membrane between two Schwann cells which is known as the Node of Ranvier
• Myelin accelerates AP propagation because it blocks leakage of current between nodes, enabling depolarizing current to spread without decrement.
• It also insulates axon, preventing charge build-up on membrane between nodes, making it easier for current to spread to next node.
• Action potentials "jump" from node to node, massively increasing conduction velocity.

Synapses

• An action potential depolarizes the axon terminal
• The depolarization opens voltage-gated Ca2+ channels and Ca2+ enters the cell
• Calcium entry triggers exocytosis of synaptic vesicle contents.
• Neurotransmitter diffuses across the synaptic cleft and binds with receptors on the post synaptic cell
• Neurotransmitter binding initiates a response in the postsynaptic cell
• Presynaptic transmitter release occurs in active zones
• Synaptic vesicles are filled with neurotransmitter
• Postsynaptic ligand-gated cation channels are in the nerve terminal in the dendrite
• Neuron receives many excitatory synaptic inputs (bouton synapses)

Synapses and Thresholds

• In vivo synaptic inputs and individual neurons membrane properties determine whether a cell will reach threshold or not
• Synaptic potentials are graded and can summate
• The balance of synaptic inputs coming into the soma and dendrites determines whether an action potential is initiated at the axon hillock
• he main excitatory neurotransmitter is glutamate
• In these synapses binding of the ligand (GABA) triggers opening of chloride channels, prevents depolarisation Ligand gated:
• Major inhibitory neurotransmitters are Gamma amino butyric acid (GABA), and glycine and ligand gated CI- channels (e.g. GABAA receptor) which are found on the neuron soma and proximal dendrites close to the axon hillock

Learning Objectives

• Describe the events of an action potential, linking changes in membrane potential with channel opening/closing and ion permeability.
• Explain the significance of a neuron reaching threshold.
• Explain why action potentials are "all or none".
• Explain the significance of the axon hillock.
• Explain the significance and physiological basis of absolute and relative refractory periods.
• Outline the role of myelin and explain differences in action potential propagation in myelinated vs unmyelinated axons.
• Describe synaptic structure and relate to function.
• Describe the sequence of events in synaptic transmission.
• Describe the concept of summation of synaptic potentials.