Membrane Potentials 2024 PDF RCSI

RCSI Royal College of Surgeons in Ireland Medical University of Bahrain Membrane Potentials Class Year 1 Course The Body: Movement & Function Code MED 1 - 102 Title Membrane Potentials Lecturer Dr. Patrick Wal...

RCSI Royal College of Surgeons in Ireland Medical University of Bahrain Membrane Potentials Class Year 1 Course The Body: Movement & Function Code MED 1 - 102 Title Membrane Potentials Lecturer Dr. Patrick Walsh Date November 2024 Learning Objectives  Describe the physicochemical properties of nerve cell membranes  Differentiate between active and passive transport mechanisms  Describe, both qualitatively and quantitatively, the transmembrane gradients for major ions  Describe the Na+-K+ pump as a driving force for membrane potential, transporters, and exchangers Cell (“plasma”) membrane 3 – 10 nm Cell (“plasma”) membrane Sherwood, Human Physiology Cell (“plasma”) membrane Sherwood, Human Physiology  PLASMA MEMBRANE All cells surrounded by fluid lipid-protein bi-layer Functions o Forms basic structural barrier enclosing cell o Serves as barrier to free passage of substances o Cell can maintain different mixtures of substances inside and outside (nutrients, waste products) o Fluidity of membrane/cell o Communication between cells o Response to external stimuli Membrane proteins o Integral / transmembrane o Extrinsic / peripheral  TRANSPORT ACROSS MEMBRANES Diffusion (e.g., O2, CO2, lipid (fat)-soluble) Protein-mediated membrane transport – Channel or Carrier proteins Guyton & Hall: Textbook of Medical Physiology  TRANSPORT ACROSS MEMBRANES Diffusion (e.g., O2, CO2, lipid (fat)-soluble) Protein-mediated membrane transport – Channel or Carrier proteins Endocytosis – Phagocytosis – Pinocytosis Guyton & Hall: Textbook of Medical Physiology Exocytosis  Plasma membrane - Phospholipid bilayer that encloses ce - Embedded with proteins that act as receptors/channels extracellular intracellular + + - Head (hydrophilic) choline, phosphate & glycerol Tails (hydrophobic) fatty acid nucleus  MOVEMENT ACROSS PM MEMBRANE Lipid soluble & small uncharged molecules (e.g. O2) – Freely diffusible – Movement driven by concentration gradient Charged (ions) / water soluble – Hydrophobic interior of PM prevents free movement polar nonpolar  MOVEMENT ACROSS PM MEMBRANE Lipid soluble & small uncharged molecules (e.g. O2) – Freely diffusible – Movement driven by concentration gradient Charged (ions) / water soluble – Hydrophobic interior of PM prevents free movement PM is said to be “selectively permeable”  MEMBRANE POTENTIAL Separation of opposite charges gives rise to “membrane potential” as opposite charges attract – Difference in cations (+) and anions (-) across PM extracellular intracellular + - + - + + - + - + -  MEMBRANE POTENTIAL Separation of opposite charges gives rise to “membrane potential” as opposite charges attract – Difference in cations (+) and anions (-) across PM All cells have a membrane potential o Electrical difference across membrane o Excitable cells actively induce changes o Basis for electrical excitability of nerve and muscle o Harnessed for transporting substances  MEMBRANE POTENTIAL Separation of opposite charges gives rise to “membrane potential” as opposite charges attract – Difference in cations (+) and anions (-) across PM All cells have a membrane potential o Electrical difference across membrane o Excitable cells actively induce changes o Basis for electrical excitability of nerve and muscle o Harnessed for transporting substances How? o PM “barrier” allows cells to establish differences in concentrations of key charged ions across PM o Magnitude of potential depends on degree of charge separation ABSENCE OF A MEMBRANE POTENTIAL PM Extracellular Intracellular - + - - + + + + + - + + + - + - - - - - + - + + - + - + - + - - + - + - - + - - + Electrically neutral: Despite membrane barrier, no charge difference across membrane: – therefore, no membrane potential PRESENCE OF A MEMBRANE POTENTIAL PM Extracellular Intracellular - + + - + + + - + - + + - + - + - + - - + - - + - + + - - + + - - + - + - + - - + + - - + + - Remainder of fluid Remainder of fluid electrically neutral electrically neutral Separated charges responsible for potential [RESTING] MEMBRANE POTENTIAL - RMP Cell membrane is more negative inside ECF ICF than outside – neuron is about -70 mV + - [RESTING] MEMBRANE POTENTIAL - RMP Cell membrane is more negative inside ECF ICF than outside – neuron is about -70 mV + - What is responsible? 1st: Unequal distribution of K+, Na+ and A- (large protein anions) between inside and outside of cell [RESTING] MEMBRANE POTENTIAL - RMP Cell membrane is more negative inside ECF ICF than outside – neuron is about -70 mV + - What is responsible? 1st: Unequal distribution of K+, Na+ and A- (large protein anions) between inside and outside of cell 2nd: “selective” leakiness of PM to K+ DISTRIBUTION OF IONS RESPONSIBLE FOR THE RMP ion ECF ICF K+ 5 150 Na+ 150 15 A- 0 65 Values in mM Na+ / K+ ATPase (pump) establishes K+ & Na+ concentrations across PM Membrane-spanning enzyme 3 Na+ Transports Na+ out, K+ in ECF 3 Na+ out for 2 K+ in – uses energy (ATP) – 200 million ions/sec Establishes concentration ICF gradients for Na+ and K+ 2 K+ Na+ / K+ ATPase Na-K pump RMP CONT. Unequal transport of positive ions by Na+/K+- ATPase also generates a small potential – inside becomes a little negatively charged with regards outside because of 3Na+ out for 2K+ in RMP CONT. Unequal transport of positive ions by Na+/K+- ATPase also generates a small potential – inside becomes a little negatively charged with regards outside because of 3Na+ out for 2K+ in But: What is responsible for most of the potential? Diffusion of K+ out of cell down concentration gradient established by pump – Leaves inside more negative  ECF ICF Concentration + - gradient for K+ K+ + - K+ + - + - + - + - A- PM IS LEAKY TO K+ But doesn’t PM stop ion movement? Relative ion ECF ICF permeability K+ 5 150 50-75 Na+ 150 15 1 A- 0 65 0 Despite “barrier”, PM contains many K+ leak channels, Allows diffusion of K+ “at rest” out of cell down its concentration gradient  ECF ICF Concentration + - gradient for K+ K+ + - K+ + - + - + - + - A- EFFECT OF K+ MOVEMENT ON MP K+ leaks out because of large concentration gradient, making inside negative A- (cannot pass) are left behind – further increases inside negativity Resting membrane potential is -70 mV  ADDITIONAL CONTRIBUTORS TO NEGATIVE MEMBRANE POTENTIAL* Membrane constituents also + contribute to negative inner membrane potential – Phosphatidylinositol (PIP2) - 2 PS - PIP - – Phosphatidylserine (PS) Both provide negative charge to inner portion of plasma membrane *not essential to know this NERNST EQUILIBRIUM Chemical gradient acts as a driving force for diffusion of K+ out of the cell ECF ICF Concentration + - gradient for K+ K+ + - K+ + - + - NERNST EQUILIBRIUM Chemical gradient acts as a driving force for diffusion of K+ out of the cell The residual negative charge acts as a electrical driving force drawing K+ back into the cell ECF ICF + Electrical Concentration gradient - gradient for K+ + K+ - K+ + - + - NERNST EQUILIBRIUM Chemical gradient acts as a driving force for diffusion of K+ out of the cell The residual negative charge acts as a electrical driving force drawing K+ back into the cell Equilibrium: electrical force balances chemical force, no net transport NERNST EQUATION Co E = + 61 x log Ci 5mM E = Equilibrium potential for ion in mV EK+ = 61 x log 61 = constant: 150mM incorporating Gas constant R; absolute temperature (T), ions valence when the valence is +1: as we have Na+/K+(z), the Faraday constant and logarithmic conversion (natural to base 10) 61 = (RT/zF) Co = conc. ion outside Ci = conc. ion inside NERNST EQUATION Co E = + 61 x log Ci 5mM E = Equilibrium potential for ion in mV EK+ = 61 x log 61 = constant: 150mM incorporating Gas constant R; absolute temperature (T), ions valence when the EK+ = - 90 mV valence is +1: as we have Na+/K+(z), the Faraday constant and logarithmic conversion (natural to base 10) 61 = (RT/zF) Co = conc. ion outside Ci = conc. ion inside WHAT ABOUT Na ? + Na+ is concentrated outside cell Concentration and electrical gradient would “drive” Na+ into cell 150mM ENa+ = 61 x log 15mM WHAT ABOUT Na ? + Na+ is concentrated outside cell Concentration and electrical gradient would “drive” Na+ into cell 150mM ENa+ = 61 x log 15mM ENa+ = 60 mV WHAT ABOUT Na ? + Na+ is concentrated outside cell Concentration and electrical gradient would “drive” Na+ into cell But, PM is very little permeable to Na+ – Very few leak channels for sodium! ECF ICF Electrochemical + - gradient for Na+ Na+ + - + - Na+ + - + - + - NERNST EQUATION Why is the K+ equilibrium potential important? The resting membrane potential is always close to the potassium equilibrium potential If the membrane becomes permeable to another ion, it will „move toward“ its equilibrium potential The membrane potential will change as a result So, if you open a channel for Na+ it will „drive“ the membrane potential toward the ENa+ (i.e. membrane potential will go from negative to positive) The sodium-potassium ATPase is a plasma membrane-spanning enzyme and is essential to preserve the ionic gradients across the cell membrane. What ions are transported via the sodium-potassium ATPase and in what direction? A. Three Ca2+ ions out of the cell and two K+ ions into the cell B. Three Cl- ions out of the cell and two Na+ ions into the cell C. Three Na+ ions out of the cell and two K+ ions into the cell B. Two Ca2+ ions out of the cell and two K+ ions into the cell E. Two Na+ ions out of the cell and three K+ ions into the cell The sodium-potassium ATPase is a plasma membrane-spanning enzyme and is essential to preserve the ionic gradients across the cell membrane. What ions are transported via the sodium-potassium ATPase and in what direction? A. Three Ca2+ ions out of the cell and two K+ ions into the cell B. Three Cl- ions out of the cell and two Na+ ions into the cell C. Three Na+ ions out of the cell and two K+ ions into the cell B. Two Ca2+ ions out of the cell and two K+ ions into the cell E. Two Na+ ions out of the cell and three K+ ions into the cell MEMBRANE POTENTIAL CHANGES Depolarisation – more positive membrane potential Hyperpolarisation – more negative membrane potential Repolarisation – Restores the potential  +60 +50 +40 Membrane potential +30 +20 +10 0 -10 -20 -30 -40 Resting Membrane Potential -50 -60 -70 +- -80 -90 -+  +60 +50 +40 Membrane potential +30 +20 +10 0 -10 -20 -30 -40 Resting Membrane Potential - -50 -60 -70 + -80 -90 -+ Hyperpolarization  +60 Depolarization +50 +40 Membrane potential +30 +20 +10 0 -10 -20 -30 -40 Resting Membrane Potential -50 -60 -70 +- -80 -90 -+ Hyperpolarization NA-K PUMP IS THE MAJOR DRIVING FORCE FOR TRANSPORT PROCESSES ACROSS MEMBANES Cell „cashes in“ chemical gradient of Na+ to transport substances into cell Cotransporters – e.g. Na+-Glucose cotransporter Na+-glucose co-transporter (SGLT) Na+-amino acid co-transporter NA-K PUMP IS THE MAJOR DRIVING FORCE FOR TRANSPORT PROCESSES ACROSS MEMBANES Cell „cashes in“ chemical gradient of Na+ to transport substances into cell Exchangers – e.g. Na+-Ca2+ exchanger Na+-Ca2+ exchanger (NCX) Na+-H+ exchanger (NHE)  Classes of ion channels Leak channel – e.g. K+ leak channel K+ Voltage-gated channel Na+ – e.g. Voltage-gated sodium- channel (VGSC) Ligand-gated channel NT Na+ – e.g. Acetylcholine receptor EXAMPLES OF DRUGS MODIFYING VOLTAGE- SENSITIVE ION CHANNELS Local anaesthetics (inhibit voltage-gated sodium (Na+ channels, i.e. Xylocaine/Lidocaine) Ca2+-channel blockers (antihypertensive drugs, i.e. nifedipine) RECOMMENDED READING MATERIALS FUN1: PHYSIOLOGY Ganong, Ganong’s review of medical physiology, Chapter 4 – http://accessmedicine.mhmedical.com.proxy.library.rcsi.ie/content.aspx?bookid= 393&sectionid=39736740 Human Physiology by Lauralee Sherwood, Brooks/Cole-Cengage Learning Ch. 4 & 5 – https://www-dawsonera-com.proxy.library.rcsi.ie/readonline/9781408088838/startPage/62 Guyton & Hall, Medical Physiology, Chapter 4 & 5, in-depth reading – https://www-clinicalkey-com.proxy.library.rcsi.ie/#!/content/book/3-s2.0-B9781455770052000 056 – (click-through library-proxy: https://www.rcsi.ie/index.jsp?p=108&n=429 : Search term:‘Guyton’) Online resources: Resting membrane potential (disregard the concentration gradients as illustrated here for the squid): http://sites.sinauer.com/neuroscience5e/animations02.01.html Ion channels and excitable cells: http://www.nature.com/scitable/topicpage/ion-channels-and-excitable-cells-14406097