Lecture 3 - The Action Potential PDF

Introduction to Behavioral Neuroscience PSYC 211 Lecture 3 of 24 – The Action Potential Chapter 3, section 2 (p79-89) Professor Jonathan Britt Questions? Concerns? Please write to [email protected] 1 TA Led Review Conferences Date Day...

Introduction to Behavioral Neuroscience PSYC 211 Lecture 3 of 24 – The Action Potential Chapter 3, section 2 (p79-89) Professor Jonathan Britt Questions? Concerns? Please write to [email protected] 1 TA Led Review Conferences Date Day Topic Time & Location Always 6:00 -8:00 pm Sept 12 Thursday Neurons & Receptors Sept 19 Thursday Neurotransmitters & Drugs MCMED 504 Sept 26 Thursday Pre-Midterm 1 Oct 10 Thursday Vision & Hearing MCMED 504 Oct 29 Tuesday Hunger & Sex MDHAR G-10 Nov 7 Thursday Pre-Midterm 2 Nov 19 Tuesday Language & Emotions MDHAR G-10 Nov 26 Tuesday Neurological Disorders MCMED 504 Dec 5 Thursday Pre-Final Exam TAs do not typically record these sessions, but they do post their PowerPoint presentations on MyCourses. 2 3  VISUALIZING NEURONS Camillo Golgi & Santiago Ramón y Cajal won the Nobel Prize in 1906 for their work on the structure of the nervous system. Their work was made possible by the discovery of the Golgi stain - a mixture of silver nitrate and potassium chromate that causes 2% of brain cells to darken in color. This mixture generates silver chromate, which can crystallize inside of neurons, highlighting every nook and cranny. snowflake a familiar ice crystal Hippocampus Retina Pyramidal cell 4  CRYSTALLIZATION Crystallization is the process of atoms or molecules arranging into a well-defined, rigid crystal lattice in order to minimize their energetic state. Water molecules crystalize when they freeze, and the unique way they arrange themselves causes ice to be larger than water. The crystallization of silver chromate (i.e., the Golgi stain) is valuable for scientists because it is a rare event (it only happens in about 2% of neurons) and the crystal structure is black in color (making the structure of these neurons clearly visible).  BASIC STRUCTURE OF THE NEURON 2. Dendrites are branched, treelike extensions from the soma. They are responsible for collecting information relevant to the cell (i.e., sensing neurotransmitters and other stimuli in the extracellular space). 1. The soma or cell body of a neuron is where its nucleus is located. Protrusions of cell membrane extend off the soma. One of these protrusions is the axon. The others are dendrites. 3. Every neuron has only one axon, but it can branch many times. These branches are called axon collaterals. At the end of every axon (axon collateral) is an axon terminal (or terminal bouton). Axons send information to downstream cells by releasing signaling molecules (neurotransmitters) onto them from the axon terminal. The junction between an axon terminal and a downstream cell is called a synapse. 6  NEURONS HAVE A RESTING MEMBRANE POTENTIAL Voltage refers to a difference in electric charge between two points – the electrostatic potential between two points. It is measured with a voltmeter (oscilloscope). Voltmeters let a negligible amount of electricity to pass through them (from one wire to the other). extracellular fluid The amount of resistance needed to allow just a little bit of electricity to flow indicates the charge difference (the voltage) between the two wires (measured in millivolts, mV). When there is some voltage (a charge difference between two points), it makes charged particles want to move to neutralize the charge difference. Cell membranes prevent this from happening. Ions cannot cross cell membranes unless there is an open door they can pass through. Measurements of voltage are always relative - the charge difference between two points. By convention, one spot is always labeled ground and is said to have a charge of 0 mV. The extracellular fluid of the brain is always considered to have a charge of 0 mV. Relative to the extracellular fluid (0 mV), neurons have a resting membrane potential of -40 to -90 mV. This means that the voltage (the electrostatic pressure) across the membrane makes positively charged ions want to enter the cell and negatively charged ions want to leave the cell. 7  Ions and Ion Channels Ion - an atom or molecule that has a net electrical charge. Ions move around freely in water. » Cations are positively charged » Anions are negatively charged Electrostatic pressure – the attractive force between ions that are oppositely charged (i.e., positive and negative) and the repulsive force between ions that are similarly charged (e.g., positive and positive). Ion channels – Proteins that form a pore (a hole) through which ions can pass. These proteins are placed in the cell membrane. When open, they let specific ions freely flow in and out of the cell. Most ion channels are bidirectional (two-way doors). Leak channel - An ion channel that permanently stays open. Potassium leak channels selectively let potassium ions freely flow in and out of the cell. All ion channels are proteins that are encoded in a cell’s DNA. 8  THE ATOMIC COMPOSITION OF CELLS Most of the atoms in cells are: 59% Hydrogen (H) 24% Oxygen (O) 11% Carbon (C) 4% Nitrogen (N) 2% Others (phosphorus, sulfur, …) A handful of other atoms are important for understanding how neurons work. These other atoms form salts when dry. In water they separate into ions. Important positively charged ions Important negatively charged ions monovalent cations: monovalent anions: sodium (Na+), potassium (K+) chloride (Cl-) divalent cations : calcium (Ca2+), magnesium (Mg2+) Potassium is colored in blue because it is the only one of these ions that is more abundant inside of cells. The others are more abundant in the extracellular space. 9 THE BUILDING BLOCKS OF ORDINARY MATTER 10  ALL CELLS HAVE A RESTING MEMBRANE POTENTIAL – A CHARGE DIFFERENCE ACROSS THE CELL MEMBRANE The cell membrane is a phospholipid bilayer. The intercellular fluid of all cells It is impermeable to atoms and molecules contains lots of negatively charged that readily dissolve in water, such as Cl- nucleic acids and amino acids. K+ nucleic acids, amino acids, and ions. Na+ There are dissolved salts Cl- Na+ inside and outside of cells Cl- (primarily Na+ Cl- and K+ Cl-). Cl- Cl- Na+ K+ K+ There are more negative K+ Cl- charges in a cell than K+ Cl- nucleic acids outside, which causes Cl- & Na+ intracellular Cl- ions to K+ amino acids hug the cell membrane. Na+ Cl- Cl- Na+ K+ Na+ Most cells in the world Cl- are like this and have a Cl- Cl- Cl- membrane potential Na+ K+ around -20 mV. Inside cells is intracellular fluid. Cl- This charge difference across the membrane Outside cells is extracellular fluid. makes negative ions want to leave the cell and positive ions want to enter the cell. 11  NEURONS HAVE AN ESPECIALLY NEGATIVE MEMBRANE POTENTIAL Unlike other cells, the membrane potential of neurons is between -40 mV and -80 mV. How and why do neurons create this especially negative resting membrane potential? Why? To be able to communicate very quickly from one end of the cell to the other. Consider the sensation of being touched, which starts in your skin. Some of your touch neurons are 2 meters long. To be helpful, they need a way to pass information down the length of their axon very quickly. How? Neurons create an electrical potential across their membrane using two proteins: – sodium potassium pump – potassium leak channel The rapid propagation of information down the length of an axon is called an action potential. It involves two other proteins: – voltage gated sodium channel – voltage-gated potassium channel Action potentials trigger the release of neurotransmitter. This involves another protein: – voltage-gated calcium channel Today’s lecture is the story of these five proteins. 12  THE SODIUM POTASSIUM PUMP Neurons fill their cell membrane with a unique protein called the sodium-potassium pump. It continually pumps sodium ions out of the cell and potassium ions into the cell. It uses ATP for energy, forcing these ions to move where they otherwise wouldn’t. 13  THE SODIUM POTASSIUM PUMP Here, I removed all the Cl- ions to simplify the picture, but Cl- is still around. Na+ The sodium potassium pump makes Na+ the concentration of K+ ions 30x Na+ higher inside the cell than out. K+ K+ K+ It also makes the concentration of Na+ ions 15x more concentrated (K+ in) K+ Na+ outside the cell than in. Na+ (Na+ out) K+ These concentration gradients never change, never ever. Na+ K+ K+ Na+ There are so many of these ions inside every K+ neuron (hundreds of trillions of them) that even if millions of ions exchange places Na+ Na+ (which frequently happens), there is always 30x more K+ ions inside the cell than out 15x more Na+ ions outside the cell than in Remember this absolute! It never changes. 14  CONCENTRATION GRADIENTS In the grand scheme of things, sodium Na+ potassium pumps don’t change the membrane potential very much on their own. Na+ Na+ K+ K+ They merely create concentration gradients. K+ Potassium is concentrated in. K+ (K+ in) Sodium is concentrated out. Na+ Na+ (Na+ out) K+ But these concentration gradients Na+ K+ generate a force: the force of diffusion. K+ Na+ K+ Na+ Na+ 15  THE FORCE OF DIFFUSION Diffusion - if there is a concentration gradient and no forces or barriers in the way, then atoms and molecules will move, on average, from regions of high concentration to regions of low concentration 16  POTASSIUM LEAK CHANNELS Neurons fill their cell membrane with a protein called the potassium leak channel. Potassium leak channels are permanently (K+ out) open ion channels that freely let K+ ions enter or leave the cell. Na+ Na+ Since K+ ions are 30x more concentrated Na+ inside the cell than out, they are much more K+ K+ likely to leave the cell than enter it. K+ K+ This is the force of diffusion. Na+ K+ Na+ The force of diffusion competes with force of electrostatic pressure. Na+ K+ K+ ions leave the cell because of diffusion. K+ Na+ But they enter the cell because it is negatively charged inside relative to outside. K+ Na+ Na+ These forces become equal and opposite when the membrane potential falls to -90 mV. (K+ out) 17 THE BALANCE OF DIFFUSION AND ELECTROSTATIC ENERGY When a neuron’s membrane potential equals -90 mV, there is no net movement of K+ ions: (K+ out) the amount leaving = the amount entering. Na+ When the membrane potential is less negative Na+ than -90mV, the force of diffusion Na+ K+ outcompetes electrostatic pressure, and more K+ K+ ions leave the cell than enter it. K+ K+ When the membrane potential is more Na+ negative than -90mV, the force of electrostatic K+ Na+ pressure gets the upper hand, and more K+ ions enter the cell than leave it. Na+ K+ K+ can always freely move in and out through K+ Na+ leak channels, but the amount coming in equals the amount going out when the K+ membrane potential equals -90 mV. Na+ Na+ (K+ out) 18  THE RESTING MEMBRANE POTENTIAL The resting membrane potential of most (K+ out) neurons is not -90 mV, but typically Na+ somewhere between -40 mV and -80 mV. Na+ This is because other ions (primarily Na+) Na+ K+ continuously flow into neurons through other K+ types of ion channels and pumps. K+ K+ But it is the permeability of the membrane to Na+ K+ Na+ K+ ions that largely determines the resting membrane potential. Na+ When a neuron opens up more K+ channels, K+ the membrane potential falls closer to -90 mV. K+ Na+ When a neuron removes some K+ channels K+ from the membrane, the membrane potential Na+ Na+ becomes less negative. (K+ out) 19  DEFINITIONS Membrane Electrical charge across a cell membrane potential The difference in electrical potential inside and outside the cell Resting Membrane potential of a neuron when it is at rest membrane (i.e., not actively receiving or transmitting potential messages). Most neurons have a resting membrane potential between -40 and -80 mV. 20  THE NEURONAL RESTING MEMBRANE POTENTIAL In summary, two proteins are responsible for setting up and maintaining the resting membrane potential of neurons: 1) Sodium-Potassium transporters (use ATP to concentrate potassium inside the cell and sodium outside the cell) The number of these pumps and their activity is never a limiting factor for neurons. The concentration differences they create (30x more K+ in than out and 15x more Na+ out than in) never change, no matter what, unless the cell dies. 2) Potassium leak channels (always open; the number of these ion channels largely determines the resting membrane potential) The cell membrane of neurons is full of leak channels that are selectively permeable to K+. If K+ was the only ion that could cross the membrane, the membrane potential would settle at -90 mV, because this is when the force of diffusion pushing K+ out is equal and opposite to the electrostatic force pushing K+ in. The resting membrane potential of most neurons is less negative than -90 mV because other ions cross the membrane through other types of ion channels and pumps. The more K+ leak channels a neuron has, the more permeable it will be to K+ relative to other ions and the closer its membrane potential will be to -90 mV. 21  0 mV -70 mV amino acids & nucleic acids This is the situation for a neuron at rest. Potassium is more abundant inside the cell. Sodium and chloride are more abundant outside. Now what does it mean for a neuron to be active? What generates the action potential and how does it propagate down the axon? 22  RECEPTORS Many other proteins on the cell membrane act as receptors (sensors). Receptors are sensitive to some aspect of the extracellular environment. All cells use receptors to detect and pull in nutrients from the extracellular space. Nutrients include proteins, fats, sugars, vitamins, and minerals. Many features of the external environment are informative but not nutritious. Neurons put receptors on their cell membrane, primarily on their dendrites, to sense these stimuli, to gain a better understanding of the world around them. 23  ION CHANNEL RECEPTORS A somewhat unique feature of neurons is their use of receptors that are ion channels. The dendrites of most neurons are full of receptors that are ion channels. When activated, these receptors change shape and open a pore through which ions can flow, in or out. These ion channels are gated by something (unlike leak channels). When these receptors get activated (perhaps by touch, sound, neurotransmitter binding, or something else), the gate briefly opens, allowing specific ions to flow through the pore of the ion channel receptor. If an activated receptor allows positively charged Na+ ions to flow freely, they rush into the cell on account of diffusion and electrostatic pressure. A large rapid influx of Na+ ions through a bunch of activated receptors will depolarize the membrane potential (make it less negative). 24  MEMBRANE DEPOLARIZATION Depolarization When the membrane potential of a cell becomes less negative than it normally is at rest. The activation of a receptor that allows positively charged Na+ ions to enter the cell will depolarize the membrane, perhaps from -70 mV to -60 mV. Why is depolarization of the membrane from -70 mV to -60 mV important? How long will this change in the membrane potential last? 25  CHANGES IN THE MEMBRANE POTENTIAL Changes to the membrane potential are always transient (short lived). Neurons are quick to return to their resting state because K+ leak channels are always open. K+ can always flow across the membrane – in either direction – through leak channels. The abundance of K+ leak channels ensures that neurons never deviate from their resting membrane potential for very long. An influx of Na+ ions through an activated receptor will only transiently depolarize the membrane, since K+ ions immediately react to this change in membrane potential and leave the cell through leak channels, thus restoring the resting membrane potential. If leak channels are always quick to counteract changes in the membrane potential, what is the point of receptor activation  Na+ influx  membrane depolarization? 26  VOLTAGE-GATED ION CHANNELS Changes in the membrane potential are super important because neurons express a variety of voltage-gated ion channels. The gate on these channels is electrically charged, so it opens (and closes) in response to changes in the membrane potential. The 3 most important voltage-gated ion channels are the… 1) Voltage-gated sodium channel (used to initiate and propagate the action potential) 2) Voltage-gated potassium channel (to quickly restore the resting membrane potential) 3) Voltage-gated calcium channel (to trigger the release of neurotransmitter) These are all proteins encoded in the genome. The first two line the entire length of the axon. It is rare to find them anywhere else. The last one, the voltage-gated calcium channel, is primarily found at the very end of the axon: the axon terminal. There are not many voltage-gated ion channels on cell bodies and dendrites. 27  THE VOLTAGE-GATED SODIUM CHANNEL cover the entire length of the axon + + + + + + + + + + + + + + + + + + + + + +++++ ++++ +++++ + +++++ ----- ----- ++ ----- ----- ----+ +---- +++++ + +++++ + + + ++ ++ + + + + The gate opens when the At rest, the electrically charged gate membrane is depolarized to The gate opens for no more than is pulled closed by the negatively about -40 mV. The open pore half a millisecond before the pore charged interior of the cell. allows Na+ ions to rush into becomes clogged by a ball on a the cell, further depolarizing chain. This ball will clog the pore But if Na+ comes in through an the membrane. until the membrane potential gets activated receptor, depolarizing the A receptor started the back down to -70 mV (which will membrane even for a brief moment, depolarization. Voltage-gated take another half millisecond). this gate may not stay closed. Na+ channels continue it. 28  THE VOLTAGE-GATED SODIUM CHANNEL Voltage-gated sodium channels line the entire length of the axon. There are tons of them where the axon connects to the soma – the axon hillock – where the action potential starts. If receptors (on the dendrites or soma) let in enough Na+ ions to depolarize membrane of the axon hillock (to around -40 mV), then voltage-gated Na+ channels will start opening, letting in more Na+ and further depolarizing the membrane. The influx of Na+ through voltage-gated sodium channels starts a chain reaction that propagates down the entire length of the axon. The Na+ influx through the first channels in the axon hillock trigger the next ones to open, which trigger the next ones to open, and so on down the axon. Axon hillock 29  THE ACTION POTENTIAL Axonal membranes contain more voltage-gated sodium channels than potassium leak channels. So, when voltage-gated sodium channels open (during the action potential), the membrane briefly becomes more permeable to sodium than potassium. Sodium ions are 15x more concentrated outside the cell than in. At rest, sodium ions want to enter the cell because of diffusion and electrostatic pressure. If they have a way in, they will keep coming in until the inside of the cell becomes +60 mV. This is when the forces of diffusion and electrostatic pressure acting on Na+ cancel out. Neurons never actually reach +60 mV because their voltage-gated sodium channels get clogged by the ball and chain. In the ½ millisecond they are open, the membrane potential reaches +40 mV. Note that there are two ways to prevent current flow through a voltage-gated sodium channel. – The pore closes whenever the membrane potential is more negative than -40 mV. – And the pore gets clogged within a ½ millisecond after opening. When this happens, the receptor is said to be inactivated. Inactivation persists until the membrane potential returns to rest. The typical chain of events is Receptor state: closed  open  inactivated  closed Triggering event: -40mV  ½ ms later 