Membrane Potential and Action Potentials in Nervous System

Membrane Potential (Vm)

• The membrane potential (Vm) represents the voltage generated due to the distribution of negative and positive charges lining the inner and outer membranes of cells.
  • Measured value is based on the inner membrane's charges relative to the outer membrane's charges.
  • The unit of measurement is millivolts (mV).
  • All cells exhibit a membrane potential (Vm).

Resting Membrane Potential

• The resting membrane potential is defined as the Vm of a cell when it is not being stimulated or inhibited.
• The distribution of potassium (K⁺) plays the biggest role in establishing the resting membrane potential:
  • Concentration of potassium ions in the intracellular fluid: [K⁺] = -135 mEq/L
  • Concentration of potassium ions in the extracellular fluid: [K⁺] = -5 mEq/L
  • Permeability of potassium: P_K = 1.0 (relative value at rest).
• Other ions' contributions (sodium [Na⁺] and chloride [Cl^-]) are smaller in comparison:
  • Intracellular sodium concentration: [Na⁺] = -15 mEq/L.
  • Extracellular sodium concentration: [Na⁺] = 140 mEq/L.
  • Sodium permeability: P_Na = -0.05 (relative value at rest).
  • Intracellular chloride concentration: [Cl^-] = ~10 mEq/L.
  • Extracellular chloride concentration: [Cl^-] = -100 mEq/L.
  • Chloride permeability: P_Cl = ~0.45 (relative value at rest).
• The Na⁺/K⁺ pump's role is to create and maintain concentration gradients for Na⁺ and K⁺ ions but is NOT responsible for resting Vm.
  • This assertion corrects common misconceptions found in literature.
• Chloride concentration gradients are also maintained similarly.

Determinants of Vm

• The resting Vm is dictated by:
  1. The size of the concentration gradients of ions.
  2. The size of the permeabilities of the membrane to those ions.
• Passive transport of ions via ion channels primarily establishes resting Vm:
  • K⁺ is transported out of the cell during resting conditions, greatly influencing Vm due to its high permeability.
  • The outer membrane holds a large amount of positive charge due to potassium transport, which dictates its influence on resting Vm.
  • Na⁺ enters the cell but at a lower rate, resulting in a small contribution to Vm due to its limited permeability during resting conditions.
  • Cl^- also enters, but its influence is similarly limited by its permeability despite a larger negative charge on the inner membrane.

Goldman-Hodgkin-Katz (GHK) Equation

• The GHK equation predicts Vm based on the permeability and concentration of various ions:
  ext{Vm} = rac{RT}{F} ext{ln} \left( \frac{P_K [K^+] + P_{Na} [Na^+] + P_{Cl} [Cl^-]}{P_K + P_{Na} + P_{Cl}} \right)
• Using average values for Na⁺, K⁺, and Cl^- in neurons, resting Vm would be approximately -65 mV; variations can occur between -40 mV to -90 mV due to concentration and permeability changes.

Equilibrium and Nernst Potential

• The equilibrium potential (E_X) or Nernst potential of an ion is the membrane potential at which there is no net movement of that ion.
  • It occurs when the electrical driving force balances the chemical driving force.
• The electrical driving force on ions depends on their charge relative to the membrane's charge:
  • Positively charged ions are attracted to negative charges and repelled by positive charges.
  • Negatively charged ions are attracted to positive charges and repelled by negative charges.
• The chemical driving force on ions reflects concentration gradients which drive passive movement through ion channels.

Nernst Equation

• The Nernst equation calculates the equilibrium potential: E_X = rac{RT}{zF} ext{ln} \left( \frac{[X]_o}{[X]_i} \right)
  • X represents the ion of interest, and specific examples include:
  • E_Na = +60 mV (no net movement at Vm = +60 mV).
  • E_K = -90 mV (no net movement at Vm = -90 mV).
  • E_Cl = -70 mV (no net movement at Vm = -70 mV).
• Ion movement is passive towards their equilibrium potential. The more permeable an ion is, the closer Vm will be to E_X. If a cell is only permeable to one ion, then Vm will equal E_X of that ion.

Changes in Vm

• Methods for changing Vm values include:
  1. Altering ion transport.
  2. Adjusting the concentration gradients of ions.
  3. Modifying the permeability of ions.
• Depolarization occurs when Vm becomes more positive:
  • The inner membrane becomes either more positive or less negative, and the outer membrane becomes less positive or more negative.
• Hyperpolarization occurs when Vm becomes more negative:
  • The inner membrane becomes more negative or less positive, and the outer membrane becomes more positive or less negative.
• Repolarization signifies Vm returning toward resting Vm following a change in Vm.

Action Potential

• The action potential is characterized as a local, very large, and rapid depolarization followed by repolarization.
• Only specific cells, such as neurons and muscle cells, can generate action potentials.

Threshold

• The threshold is the level of depolarized Vm necessary to initiate an action potential.
  • Action potentials exhibit an all-or-none response: either they are generated if the threshold is reached, or they are not generated.

Generation and Dynamics of Action Potential in Neurons

1. Neuron stimulation causes Vm to depolarize until the threshold is reached.
2. Voltage-gated Na⁺ channels quickly activate, leading to an increase in Na⁺ permeability.
3. This results in a rapid influx of Na⁺ into the cell, causing significant and swift depolarization of Vm, moving towards E_Na.
4. As Vm approaches maximum depolarization, voltage-gated Na⁺ channels inactivate, stopping Na⁺ transport.
5. Voltage-gated K⁺ channels then open more slowly, increasing K⁺ permeability, leading to K⁺ efflux and repolarization towards resting Vm, beginning at the action potential peak.
6. The action potential results in an after-hyperpolarization, where Vm becomes slightly more negative than the resting state.
7. Resting Vm is reestablished by the channels responsible for maintaining it.

Action Potential Frequency

• The maximum frequency of action potentials is governed by the refractory period:
  • A shorter refractory period leads to a greater number of action potentials.
  • Action potential frequency is directly proportional to the stimulus strength:
  • If the stimulus decreases, action potential frequency decreases.
  • If the stimulus increases, action potential frequency increases.

Types of Stimuli

• Sub-threshold stimulus: A slight stimulus that doesn't reach threshold, leading to no action potential.
• Threshold stimulus: A stimulus that meets the minimum requirement to generate one action potential.
• Submaximal stimulus: A stimulus greater than threshold but less than maximal, generating multiple action potentials without reaching the maximal frequency.
• Maximal stimulus: This stimulus elicits the maximum action potential frequency.
• Supra-maximal stimulus: This exceeds maximal stimulus levels but does not increase action potential frequency beyond the maximum limit.

Action Potential Conduction

• Action potential conduction refers to the propagation of action potentials along a membrane:
  • An action potential does not travel across a membrane; instead, it induces generation in adjacent regions, akin to falling dominos.
  • Conduction velocity depends on axon diameter and myelination:
  • Larger axons conduct action potentials faster due to a larger surface area and more voltage-gated ion channels.
  • Myelinated axons conduct action potentials faster, with higher myelination resulting in faster conduction.

Continuous Conduction

• Occurs in unmyelinated axons and excitable cell membranes:
  • Action potential in one area stimulates adjacent regions to depolarize, with velocities less than 2 meters/sec.

Dynamics of Continuous Conduction

1. Sodium ions from an action potential diffuse into the adjacent region, causing depolarization.
2. When the threshold is reached in the new region, another action potential is generated.
3. This process continues unidirectionally.

Saltatory Conduction

• Ensured by the refractory period, this conduction occurs in myelinated axons:
  • Action potentials form at the nodes of Ranvier, where voltage-gated Na⁺ and K⁺ channels are densely concentrated, allowing high conduction velocities of 3 to 120 meters/sec.

Dynamics of Saltatory Conduction

1. Sodium ions diffuse to the adjacent node from the action potential, causing depolarization.
2. Myelin sheath enables rapid diffusion of sodium, leading to action potential generation at the next node of Ranvier.
3. This conduction continues unidirectionally, ensured by the refractory state.

Synapse

• The synapse is the junction enabling communication between two cells, categorized into two types:

Electrical Synapse

• Communication occurs between two cells via gap junctions formed by two connexons (one from each cell):
  • Each connexon is assembled from six proteins called connexins.
  • These junctions allow rapid molecule passage facilitating coordination among electrically coupled cells.

Chemical Synapse

• Communication occurs through the release of neurotransmitters:
  • The presynaptic membrane carries information, while the postsynaptic membrane receives it.
  • The synaptic cleft is the tiny gap separating these membranes.

Neurotransmitters

• Chemicals released from the presynaptic cell into the synaptic cleft, produced by that cell and stored in synaptic vesicles:
  • Some gaseous neurotransmitters are produced on demand rather than stored, leading to varied release dynamics.

Synaptic Transmission

1. Action potentials travel to the presynaptic terminal, prompting voltage-gated calcium channels to open.
2. Intracellular calcium levels rise, causing synaptic vesicles to fuse with the presynaptic membrane, releasing neurotransmitters into the cleft via exocytosis.
3. Neurotransmitters diffuse across the synaptic cleft, binding to receptors on postsynaptic membranes, which modulate ion channels or lead to production of gaseous neurotransmitters.

Fate of Neurotransmitter

1. Reuptake of neurotransmitters by the presynaptic membrane for recycling.
2. Gaseous neurotransmitters are metabolized within the postsynaptic cell.
3. Reuptake inhibitors can prolong neurotransmitter action in the synaptic cleft, enhancing effects and administered when natural levels are low.

Postsynaptic Potential

• Refers to transient Vm change on the postsynaptic membrane due to neurotransmitter release:
  • Excitatory postsynaptic potential (EPSP): Depolarization caused by cation influx (e.g., Na⁺).
  • Inhibitory postsynaptic potential (IPSP): Hyperpolarization from anion influx (e.g., Cl^-) or cation efflux (e.g., K⁺).

Summation of Postsynaptic Potential

• The combined effects of multiple EPSPs and IPSPs dictate the output Vm change:
  • Spatial Summation: Multiple potentials from different synapses occurring simultaneously.
  • Temporal Summation: Multiple potentials from the same synapse occurring closely in time.

Synaptic Plasticity

• Refers to changes in the synapse's structure or function affecting neurotransmitter release or receptor numbers, which can lead to new synapse formations or synapse loss:
  • Requires a significant "event" for plasticity to occur.