Slide 1Slide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 241Bi 1 Lecture 6 Thursday, April 6, 2006Action Potentials and Single Channels2[neurotransmitter]openclosedchemical transmission atsynapses:electric fieldopenclosedelectrical transmission inaxons:actually, EMajor Roles for Ion ChannelsMonday:3The electric field across a biological membrane, compared with other electric fields in the modern world1. A “high-voltage” transmission line1 megavolt = 106 V.The ceramic insulators have a length of ~ 1 m.The field is ~ 106 V/m. 2. A biological membraneThe “resting potential” ~ the Nernst potential for K+, -60 mV.The membrane thickness is ~ 3 nm = 30 Å.The field is (6 x 10-2 V) / (3 x 10-9 m) = 2 x 107 V/m !!!Dielectric breakdown voltages (V/m)Ceramic 8 x 107Silicone Rubber 3 x 107Polyvinyl chloride 7 x 1064Little Alberts 12-32© Garland= IMPULSEThe action potential (the nerve impulse)5http://www.theory.caltech.edu/people/politzer/syll1c/syll1c.htmlToday’s reasoning employs electrical circuits6open channel = conductor=7The miniature single-channel conductors add in parallel ENa(+60 mV)GNa = Na=GNaNaNaoutsidecytosol = insidemostly K+mostly Na+GK = K EK (- 60 mV)GKKK8CEGNa+VE G E G E GG G GK K Na Na Cl ClK Na Cl  K+At DC, IC = CdV/dt = 0, soCl-peak of action potential: Na+ channels open too resting potential:K+ channels openoutsidecytosol = insideThe membrane potential at steady state(not at equilibrium) “after-hyperpolarization”: more K+ channels open9The “Na+ pump” splits ATP to make a Na+ and K+ concentration gradient A transporter protein moves a few ions for each conformational change32Little Alberts 12-10 © Garlandfrom Lecture 5What are the electrical consequences of the charge imbalance?10Every largeRvery large= =Na pump = current source11pumpchannelTo understand the Na pump’s action on the membrane potential, we treat the pump as a current source . . .and we treat the channels as resistors12ATPpumpchannelV+-V = IRBecause of the charge imbalance,The Na pump drives the membrane potential more negative(the cell “hyperpolarizes”= the pump is “electrogenic”). . . and we invoke Kirchoff’s lawCEGNa+K+Cl-outsidecytosol = inside13All I really need to know about lifeI learned in Bi 11. If you want a job done right, get a protein (Lecture 3)2. Electrical circuits explain many processes14Channel opening and closing rate constants are functions of voltage--not of time:The conformational changes are “Markov processes”.The rate constants depend instantaneously on the voltage--not on the history of the voltage.These same rate constants govern both the macroscopic (summed) behavior and the single-molecule behavior.In a real neuron, the opening and closing of the channels changes the voltage, and it takes a while to charge up the membrane capacitance (see QP1). As result, impulse propagation is solved numerically--but on the basis of rate constants derived from experiments where the voltage is held constant (“clamped”). The Hodgkin-Huxley formulation of the nerve impulse15http://nerve.bsd.uchicago.edu/nerve1.html1. Waveform at one point (V vs t)2. Hyperpolarization3. “Refractory” period (30 ms total time, vary pulse 2 duration, pulse 3 = 30 A)5. Propagation (V vs. x)6. Repetitive firing: the frequency code (lengthen pulse 1) (For robust frequency encoding, we require one additional type of K+ channel.)Simulation of the nerve impulse (“unclamped”)Francisco Bezanilla's simulation program at the Univ of Chicago:161973Max DelbruckRichard FeynmanH. A. LCarver Mead17Intracellular recording with sharp glass electrodesV = RC = 10 ms; too large!C = 1 F/cm2ER = 104 -cm2intracellularextracellular18A better way: record the current from channels directly?Feynman’s ideaA195 pA = 104 ions/ms20 msA single voltage-gated Na+ channel-80 mV-20 mVA20http://www.nobel.se/medicine/laureates/1991/press.htmlPress release for 1991 Nobel Prize in Physiology or Medicine:21Simulation of a voltage-gated K+ channelhttp://nerve.bsd.uchicago.edu/model/rotmodel.htmlFrancisco Bezanilla's simulation program at the Univ. of Chicago:22action potentialnounDate: 1926: a momentary change in electrical potential (as between the inside of a nerve cell and the extracellular medium) that occurs when a cell or tissue has been activated by a stimulus. H. A. L. prefers “impulse”23-from sense organs to the brain (Thanos Siapas, lecture 4)-within the brain-from the brain to muscles-even in a muscle or in the heart-even in the pancreasThe frequency of impulses represents signaling among cells in the nervous system.24End of Lecture