Week 2 Receptors, Graded potentials and Resting membrane potential pt3 PDF

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Week 2 lecture notes pt3...

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Charged separation: Origin of membrane potential - Some potassium diffuses out of the cell down its chemical concentration gradient and leaves behind unmatched negative charges - While ICF & ECF are more or less electrically neutral, a small difference in the number of charged ions exist between the inside and outside of the cell = charge separation Note: Charges cluster near the membrane - Slight excess of positive charges on the outside of the membrane - Slight excess of negative charges in the inside of the membrane

Electrical gradients = Electrical driving forces - Because ions carry electrical charge we also have to consider the electrical gradients that now exist across the membrane Note: Opposite charges attract, like charges repel - Charge separation (i.e due to chemical gradients) creates an electrical driving force E.g Negatively charged cell interior attracts cations and repels anions

Chemical gradient + Electrical gradient = Electrochemical gradient - We must consider both chemical and electrical forces to understand how ions move - The net driving force is a combination of both these forces

Establishing ionic gradients aka sodium potassium pump: - Primary active transport of potassium inwards and sodium outwards establishes and maintains chemical concentration gradients across the cell membrane Note: Both sodium and potassium are moving against their electrochemical gradient - As ATP is hydrolysed to Adenosine diphosphate, the protein undergoes a conformational change - 3 sodium ions are transported out of the cell - 2 potassium ions are transported into the cell Note: Establishes and maintains chemical gradients of potassium and sodium

Forces acting on individual ions (Potassium): - Potassium chemical gradient high on the inside and low on the outside - Chemical driving force acts cause net movement of potassium out of the cell - Potassium diffuses out of the cell through open leak channels Note: However, impermeant organic anions remain inside the cell - Inside of the cell becomes increasingly negatively charged due to loss of positive charges - The exterior of the cell now has slight excess of positive charges Note: This process creates the development of our membrane potential due to charge separation across the membrane - Electrical driving force attracts potassium back into the cell Note: If we only had potassium in this system the cell would eventually reach equilibrium Equilibrium occurs when the chemical and electrical driving forces are….

- Opposite in direction & equal in magnitude Note: Potassium would still be diffusing across membrane through leak channels BUT, there would be no NET flux - The membrane potential at which this theoretical condition occurs is known as the equilibrium potential

Nernst equation for potassium: - The equilibrium potential is useful as it tells us which way an ion will moves across the cell membrane at a given membrane potential Note: Equilibrium potential can be calculated from the intracellular & extracellular concentrations of the ion via the nernst equation

What about other ions? - The cell membrane is also selectively permeable for other ions such as chloride or sodium - Each of these will have their own equilibrium potentials Note: These can also be calculated using the nernst equation

Forces acting on individual ions (Sodium): - High concentration of sodium outside the cell & a low concentration inside the cell - A chemical driving force acts to cause a net movement of sodium into the cell Note: Sodium diffuses into the cell via open leak channels - As sodium diffuses into the cell, the cell becomes less negative due to an influx of positive charges - The exterior of the cell now has slight excess of positive charges Note: This process again results in the development of a membrane potential due to charge separation across the membrane - Electrical driving force attracts sodium back out of the cell, resisting the sodium influx Note: If we only had sodium our cell would eventually reach equilibrium - Equilibrium occurs because the chemical and electrical driving forces are opposite in direction & equal in magnitude Note: Sodium would still be diffusing across the membrane randomly, however there would be NO net flux - The membrane potential at which this theoretical condition occurs is known as the equilibrium potential

Nernst equation for sodium: - To get the equilibrium potential for sodium ions z = +1 - The equilibrium potential for sodium is entirely different to potassium

Summary: - The electrical potential for an ion is the potential electrical force acting to move that ion across the membrane Equilibrium potential potassium: -95mV

Equilibrium potential Sodium: +66mV Equilibrium potential Chloride (ignore for now): -90mV IMPORTANT: The net electrochemical force acting on an ion tends to move that ion across the membrane in the direction that will bring the voltage of the membrane closer to the equilibrium potential of that ion - If potassium was the only ion to cross the membrane the resting membrane potential would be -95mV - If sodium was the only ion to cross the membrane the resting membrane potential would be +66mV Note: However real cells are permeable to both meaning the resting membrane potential will fall somewhere between the range of both sodium & potassium

Typical Neuron [Potassium]: - At -70mV, the chemical force driving potassium out of the cell is > the electrical force pulling potassium in - Net outward electrochemical force acting on potassium ions - Net outward flux/current of potassium ions

Typical Neuron [Sodium]: - At -70mV, BOTH the chemical and electrical force acting on sodium are directed inwards - Net inward electrochemical force acting on sodium ions - Net inward flux/current of sodium ions

Establishment of resting membrane potential: - Imagine a cell which is only initially permeable to potassium ions - This cell would reach an equilibrium potential for potassium 0f -95mV - Now the cell becomes slightly more permeable to potassium Note: Sodium will flow into the cell, thus the inside becomes more positive - This will increase the electrochemical force driving potassium out of the cell & the electrochemical force driving sodium into the cell Note: The more potassium leaves the cell, the less sodium enters - Eventually the cell reaches a steady state, where the efflux of potassium is balanced by the influx of sodium Note: The resting membrane potential is no longer -95mV (between potassium or sodium)

Ionic currents: - The movement of ions across the membrane are called ion currents, as ions carry electrical charge across the membrane - Potassium ions flowing out of the cell = outward potassium current - Sodium ions flowing into the cell = inward sodium current Note: In a cell permeable to potassium & sodium the resting membrane potential will occur when the outward potassium current is equal to the inward sodium current

Electrochemical driving force: - The magnitude of the electrochemical force acting on a particular ion was proportional to membrane potential - equilibrium potential - So for potassium = -70mV - -95mV (+25mV positive outward current) - For sodium = -70mV - + 66mV (-136mV negative inward current) Note: At rest the electrochemical force trying to move sodium into the cell is MUCH greater than the electrochemical driving force driving potassium out of the cell

Membrane permeability: - The movement of sodium & potassium across the membrane (i.e flow of ionic current) is also dependent on the permeability of the membrane to each of these ions Note: In most cells the membrane is 25x more permeable to potassium than sodium - Despite the weak force driving potassium out of the cell, the high permeability of the membrane to potassium produces an outward current which matches the inward sodium current that is driven by a large electrochemical force but is restricted by the low sodium permeability

Goldman Hodgkin Katz equation: - The quantitative relationship between the RMP and both ion concentrations and permeabilities for a cell that is permeable to the monovalent potassium & sodium is described by this equation

Note: It is easier to think about relative permeabilites rather than absolute permeabilities so the GHK formula is often written in a different form - Means if we know relatively permeability of cell to those ions we can derive the resting potential

What about chloride? - Depending on cell type the membrane is usually quite permeable to chloride Relative permeabilities: Potassium: 1 Sodium: 0.04 Chloride: 0.45 - In cells that do not actively expell chloride, chloride diffuses into the cell via leak channels, down it’s electrochemical gradient to adjust the internal chloride to give an equal resting membrane potential - In other cells chloride is actively pumped out of the cell and contributes to the RMP Note: Can calculate RMP for such cells using GHK equation which incorporates chloride

Maintenance of the resting membrane potential: - In the absence of any other mechanism, the chemical gradients of potassium & sodium across the membrane would gradually dissipate due to diffusion - The membrane would thus become electrically neutral on both sides Note: The cell must actively transport potassium into the cell against it’s chemical concentration gradient - This is the role of the sodium potassium pump - Maintains the chemical gradients of sodium & potassium across the membrane that maintains the resting membrane potential

Sodium potassium pump: - Actively transports sodium & potassium against their gradients using ATP Note: In electrically active neurons 60-70% of cell energy budget is used to drive said pump while only 25% in other cells - Removes 3 sodium from the cell for every 2 potassium brought in (i.e is electrogenic) - As well as maintaining the RMP, the sodium pump also directly contributes to the RMP (-5 to -10mV) Note: Actively modulated by changes in sodium - Death is basically insufficient ADP to maintain the sodium potassium pump...