The Resting Neuronal Membrane PDF, Fall 2024

The Resting Neuronal Membrane Chapter 3  – Discuss the key components of the neuronal membrane – Learn about the movement of ions across the Learning neuronal membrane (cellular electricity) objectives – Understand ionic basis of the resting membran...

The Resting Neuronal Membrane Chapter 3  – Discuss the key components of the neuronal membrane – Learn about the movement of ions across the Learning neuronal membrane (cellular electricity) objectives – Understand ionic basis of the resting membrane potential – Discuss important channels found in the neuronal membrane  – Neurons communicate via electrical signals called action potentials – In order for action potentials to even be possible in the first place, we must have a baseline electrified state of neuronal cells that we call the resting membrane potential The role of electricity in the nervous system A simple reflex  – Cytosol and extracellular fluid – Water Key – Key ingredient in intracellular and extracellular fluid components – Key feature: Water is a polar solvent. – Ions: atoms or molecules with a net electrical charge of the – Cations: net positive charge neuronal – Anions: net negative charge membrane – Spheres of hydration  – The phospholipid bilayer membrane forms a barrier that isolates the neuronal cytosol from the extracellular fluid – Hydrophilic compounds – Dissolve in water due to uneven electrical charge (e.g., salt) – Hydrophobic compounds – Do not dissolve in water due to even electrical charge (e.g., oil) Key – Lipids are hydrophobic. components – Contribute to resting and action potentials of the neuronal membrane  – Proteins Key – Molecules assembled from amino acids, composing: components – Enzymes of the – Cytoskeletal elements – Receptors neuronal – Special proteins span the membrane phospholipid bilayer in neurons – Control resting and action potentials Membrane ion channel  – Protein structure overview – Amino acids (smallest ”building blocks”) joined together by: – Peptide bonds to form polypeptides Key components of the neuronal membrane  – Protein structure overview – Amino acids (smallest ”building blocks”) joined together by: – Peptide bonds to form polypeptides Key components of the neuronal membrane  – Protein structure overview – Four levels of protein structure – Primary (single file sequence of amino acids) – Secondary (coiling sequence into a helix or folding into a sheet) – Tertiary (folding helix or sheet to create a 3 dimensional shape) Key – Quaternary (the complete protein shape with various polypeptides bonded together) components of the neuronal membrane A: primary B: secondary C: tertiary D: quaternary protein structures  – Channel proteins are studded throughout the neuronal cell membrane – Polar R groups and nonpolar R groups allow them to be fitted inside the membrane – They allow for ion transport, Key selectivity, and gating (the basis of all cellular electricity!!!) components – Ion pumps are a type of channel protein of the – Formed by membrane-spanning proteins neuronal – Use energy from ATP breakdown – Neuronal signaling membrane – Issues with channel proteins are the root of MANY neurological disorders – Epilepsy Membrane ion channel – Congenital insensitivity to pain  – Diffusion Movement of – Dissolved ions distribute evenly ions across – Ions flow down concentration gradient when: – Channels are permeable to specific ions the neuronal – Concentration gradient exists across the membrane membrane  – Electricity – Electrical current influences ion movement (think ”opposites attract”/magnets) – Electrical potential (voltage) Movement of – Force exerted on charged particle ions across – Difference in charge between positive and negative side the neuronal – Electrical conductance (g) and resistance (R) – Conductance = how easy can electrical charges membrane move? – Resistance = how difficult is it for charges to move? – R = 1/g (resistance is the inverse of conductance) Movement of – Electricity – Ohm’s law I = gV ions across – I = current – g = conductance the neuronal – V = potential membrane – What if conductance is zero? – See why we need membrane protein channels?  – Definitions – Voltage: a measure of potential energy generated by separated charge – Measured between two points in volts (V) or millivolts (mV) – Called potential difference or potential – Charge difference across plasma membrane results in potential – Greater charge difference between points = higher voltage – Current: flow of electrical charge (ions) between two points (amperes/amps) – Can be used to do work Basic – Flow is dependent on voltage and resistance – Resistance: hindrance to charge flow (ohms) principles of – Insulator: substance with high electrical resistance – Conductor: substance with low electrical resistance – Ohm’s law: gives relationship of voltage, current, resistance electricity Current (I) = voltage (V)/resistance (R) – Current is directly proportional to voltage refresher – Greater the voltage (potential difference), greater the current – No net current flow between points with same potential – Current is inversely proportional to resistance – The greater the resistance, the smaller the current  – Opposite charges are attracted to each other – Energy is required to keep opposite charges separated across a membrane – Energy is liberated when the charges move toward one another – When opposite charges are separated, the system has potential energy Basic principles of electricity refresher  – Membrane potential: voltage across the neuronal membrane at any moment – Like all cells, neurons have a resting membrane potential – Unlike most other cells, neurons can rapidly change resting membrane potential Ionic basis of – Neurons are highly excitable the resting membrane potential  – Equilibrium potential (Eion) – No net movement of ions when separated by a phospholipid membrane *without channel proteins*; no charge, no voltage – If you insert K+ channels in the phospholipid bilayer, they will flow down the concentration gradient towards equilibrium and cause a relative change in charge/voltage across the membrane – Eion is the electrical potential difference that exactly balances ionic concentration gradient – The inside of the cell can end up being positively or negatively charged Ionic basis of relative to the outside at the equilibrium potential the resting membrane potential Inside of cell negatively charged at equilibrium potential for K+  – Equilibrium potential (Eion) – No net movement of ions when separated by a phospholipid membrane *without channel proteins*; no charge, no voltage – If you insert K+ channels in the phospholipid bilayer, they will flow down the concentration gradient towards equilibrium and cause a relative change in charge/voltage across the membrane – Eion is the electrical potential difference that exactly balances ionic concentration gradient – The inside of the cell can end up being positively or negatively charged Ionic basis of relative to the outside at the equilibrium potential the resting membrane potential Inside of cell positively charged at equilibrium potential for Na+  – Four important points 1. Large changes in Vm only need tiny amounts of ion concentration change/movement 2. Net difference in electrical charge is lined up at the borders of the Ionic basis of membrane surface – Think mosquitos lined up on net the resting trying to get across 3. Rate of movement of ions across membrane membrane is going to be potential determined by the membrane potential and ion equilibrium potential – Proportional to Vm – Eion 4. If the concentration difference for an ion is known, the equilibrium potential for that ion can be calculated.  – The Nernst equation – Calculates the exact value of the equilibrium potential for each ion in mV – Takes into consideration: The Nernst – Charge of the ion equation allows – Temperature – Ratio of the external and internal ion concentrations us to calculate the equilibrium potential for each ion across You may also see it as this which uses log10 instead of natural log: the neuronal membrane  – The distribution of ions across the membrane varies depending on the ion, but that concentration is consistent across the vast majority of neuronal cells – K+ more concentrated on inside, Na+ and Ca2+ more concentrated outside Ionic basis of the resting membrane potential  – How is it possible to move ions AGAINST their concentration gradient?! – The sodium-potassium pump! – 3 sodium (Na+) out, 2 potassium (K+) in, per ATP expended – An enzyme that breaks down ATP when Na+ is present – May use up to 70% of all the ATP in the entire brain! – Calcium pump actively transports Ca2+ out of cytosol. Ionic basis of – Ion pumps are the GOATs of neurophysiology the resting membrane potential Membrane permeability  – Differences in plasma membrane permeability – Slightly permeable to Na+ (through leakage channels) – 25 times more permeable to K+ than sodium (more leakage channels) – Quite permeable to Cl– – More potassium diffuses out than sodium diffuses in – As a result, the inside of the cell is more negative – Establishes resting membrane potential – Sodium-potassium pump (Na+/K+ ATPase) stabilizes resting membrane Membrane potential – Maintains concentration gradients for Na+ and K+ permeability – Three Na+ are pumped out of cell while two K+ are pumped back in  – Generating a resting membrane potential depends on (1) differences in ion concentrations inside and outside cells, and (2) differences in permeability of the plasma membrane to those ions. – Relative ion permeabilities of the membrane at rest are determined by how many channels we have for each ion – not all ions are equally easily moveable across the membrane! – Neuron membranes permeable to more than one type of ion. – Membrane permeability determines membrane potential. – Goldman equation Ionic basis of – Takes into account permeability of membrane to different ions to give a pretty accurate calculation of resting membrane potential the resting membrane potential  – Resting membrane potential of a resting neuron is approximately −70 mV – The cytoplasmic side of membrane is negatively charged relative to the outside – The actual voltage difference varies from −40 mV to −90 mV – The membrane is said to be polarized – Potential generated by: – Differences in ionic composition of ICF and ECF Membrane – Differences in plasma membrane permeability potential  – Role of membrane ion channels – Large proteins serve as selective membrane ion channels – K+ ion channel allows only K+ to pass through – Two main types of ion channels – Leakage (nongated) channels, which are always open – Gated channels, in which part of the protein changes shape to open/close the channel – Three main gated channels: chemically gated, voltage—gated, or mechanically gated Membrane ion channels  – Chemically gated (ligand-gated) channels – Open only with binding of a specific chemical (example: neurotransmitter) – Voltage-gated channels – Open and close in response to changes in membrane potential – Mechanically gated channels – Open and close in response to physical deformation of receptors, as in sensory receptors Membrane ion channels  – Chemically gated (ligand-gated) channels – Open only with binding of a specific chemical (example: neurotransmitter) – Voltage-gated channels – Open and close in response to changes in membrane potential – Mechanically gated channels – Open and close in response to physical deformation of receptors, as in sensory receptors Membrane ion channels From Dr. Zhou’s 2020 paper  – When gated channels are open, ions diffuse quickly: – Along chemical concentration gradients from higher concentration to lower concentration – Along electrical gradients toward opposite electrical charge Membrane ion channels  – The selective permeability of potassium channels is a key determinant of resting membrane potential – Many types of potassium Potassium channels – There are entire ”families” of channels different K+ channels – Example: Shaker potassium channel discovered in Drosophila fruit flies  – K+ channels: four subunits – Channel selectively permeable to K+ ions – Pore loop area important for selectivity filter – MacKinnon—2003 Nobel Prize – Mutations of specific K+ channels; inherited neurological disorders Potassium channels A: electron microscopy image of potassium channels studded in cell membrane; B: schematized structure of potassium channels  – K+ channels: four subunits – Channel selectively permeable to K+ ions – Pore loop area important for selectivity filter – MacKinnon—2003 Nobel Prize – Mutations of specific K+ channels; inherited neurological disorders Potassium channels Atomic structure of potassium channel from a top-down view. Red ball in center is a K+ ion  – Special importance of regulating external K+ concentration – Resting membrane potential is close to EK because it is mostly permeable to K+. – Membrane potential sensitive to changes in extracellular K+ – Increased extracellular K+ depolarizes membrane. Potassium channels Changes to potassium concentration around neurons are going to cause huge changes in membrane potential.  – K+ concentrations are so important to maintain that we developed 2 major mechanisms regulating the external potassium concentration: – Blood-brain barrier Potassium – Potassium spatial buffering by astrocytes channels – Consequences of K+ concentrations going out of control? – Scorpion venom – potassium channel blocker! – Lethal injection…  – Membrane potential changes when: – Concentrations of ions across membrane change – Membrane permeability to ions changes Changing the – Changes produce two types of signals – Graded potentials membrane – Incoming signals operating over short distances potential – Action potentials – Long-distance signals of axons – Changes in membrane potential are used as signals to receive, integrate, and send information Quiz hint! – Ion concentrations inside & outside of neuron membrane Questions?