1 Bi 1 Lecture 6 Thursday, April 6, 2006 Action Potentials and Single Channels

2 [neurotransmitter] open closed chemical transmission at synapses: electric field open closed electrical transmission in axons: actually,  E Major Roles for Ion Channels Monday:

3 The electric field across a biological membrane, compared with other electric fields in the modern world 1.A “high-voltage” transmission line 1 megavolt = 10 6 V. The ceramic insulators have a length of ~ 1 m. The field is ~ 10 6 V/m. 2.A biological membrane The “resting potential” ~ the Nernst potential for K +, -60 mV. The membrane thickness is ~ 3 nm = 30 Å. The field is (6 x V) / (3 x m) = 2 x 10 7 V/m !!! Dielectric breakdown voltages (V/m) Ceramic8 x 10 7 Silicone Rubber3 x 10 7 Polyvinyl chloride7 x 10 6

4 Little Alberts © Garland = IMPULSE The action potential (the nerve impulse)

5 Today’s reasoning employs electrical circuits

6 open channel=conductor =

7 The miniature single-channel conductors add in parallel E Na (+60 mV) G Na =  Na = G Na  Na outside cytosol = inside mostly K + mostly Na + G K =  K E K (- 60 mV) GKGK KK KK

8 C E G Na +  V EGEGEG GGG KKNa Cl KNaCl    K+K+ At DC, I C = CdV/dt = 0, so Cl - peak of action potential: Na + channels open too resting potential: K + channels open outside cytosol = inside The membrane potential at steady state (not at equilibrium) “after-hyperpolarization”: more K + channels open

9 The “Na + pump” splits ATP to make a Na + and K + concentration gradient A transporter protein moves a few ions for each conformational change 3 2 Little Alberts © Garland from Lecture 5 What are the electrical consequences of the charge imbalance?

10 E very large R very large == Na pump =current source

11 pump channel To understand the Na pump’s action on the membrane potential, we treat the pump as a current source... and we treat the channels as resistors

12 ATP pump channel V + -  V = IR Because 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 law C E G Na + K+K+ Cl - outside cytosol = inside

13 All I really need to know about life I learned in Bi 1 1. If you want a job done right, get a protein (Lecture 3) 2. Electrical circuits explain many processes

14 Channel 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).capacitance 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 impulse

Waveform at one point (V vs t) 2.Hyperpolarization 3.“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:

Max Delbruck Richard Feynman H. A. L Carver Mead

17 Intracellular recording with sharp glass electrodes V  = RC = 10 ms; too large! C = 1  F/cm 2 E R = 10 4  -cm 2 intracellular extracellular

18 A better way: record the current from channels directly? Feynman’s idea A

19 5 pA = 10 4 ions/ms 20 ms A single voltage-gated Na + channel -80 mV -20 mV A

20 Press release for 1991 Nobel Prize in Physiology or Medicine:

21 Simulation of a voltage-gated K + channel Francisco Bezanilla's simulation program at the Univ. of Chicago:

22 action potential noun Date: 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 pancreas The frequency of impulses represents signaling among cells in the nervous system.

24 End of Lecture 6