Neuroscience Chapter 3: The Neuronal Membrane at Rest 高毓儒 Institute of Physiology, School of Medicine National Yang-Ming University 2826-7086 yrkou@ym.edu.tw

Outline Introduction The Cast of Chemicals The Movement of Ions The Ionic Basis of the Resting Membrane Potential Review

What we are? Introduction

Example-A Simple Reflex Introduction (BF3.1)

A Simplified Structure Introduction

Structure and Function Introduction Cognition and Behavior The Nervous System Collection, Distribution and Integration The Neuron Excitation

Encoding by Frequency and Pattern A Simplified Function Introduction Encoding by Frequency and Pattern Conduction Action Potential Resting Membrane Potential

Introduction Light or Heat Conduction Electricity Generator Analogy Differences

Differential permeability to ions Channels and pumps Important Elements The Beauty Ions Bilayer membrane Differential permeability to ions Channels and pumps Differential responses

Monovalient and divalent Na , K , Ca , Cl Water and Ions The Cast of Chemicals Cations and anions Monovalient and divalent Na , K , Ca , Cl + + 2+ -

Phospholipid Membrane The Cast of Chemicals Phospholipid bilayer Hydrophilic and hydrophobic

Ion channels and ion pumps Channel Protein The Cast of Chemicals Ion channels and ion pumps

Amino acids and polypeptides Protein The Cast of Chemicals Amino acids and polypeptides

Concentration gradient Diffusion The Movement of Ions Concentration gradient

The Movement of Ions Ohm’s law: I = gV g: conductance I: currect Electrical Current The Movement of Ions Ohm’s law: I = gV g: conductance I: currect V: potential

Electrical Current The Movement of Ions g = 0 g > 0

Resting Membrane Potential Measurement Resting Membrane Potential

Equilibrium Potential Resting Membrane Potential

Equilibrium Potential Resting Membrane Potential Minuscule changes in ionic concentration 100 mM 99.99999 mM Large changes in membrane potential 0 mV 80 mV

Equilibrium Potential Resting Membrane Potential The difference occurs only at the inside and outside surface. Vm – Eion = ionic driving force

Equilibrium Potential Resting Membrane Potential + Another example: Na

Equilibrium Potential Resting Membrane Potential The Nernst equation

Resting Membrane Potential Ionic Distributions Resting Membrane Potential

Resting Membrane Potential Ionic Distributions Resting Membrane Potential + + Role of Na -K pump – an electrogenic pump

Resting Membrane Potential Ionic Distributions Resting Membrane Potential 2+ Role of Ca pump

Resting Membrane Potential Ionic Permeabilities Resting Membrane Potential + + Na and K - equilibrium potential PNa < 40 X PK The Goldman equation + +

Resting Membrane Potential Potassium Channels Resting Membrane Potential Structure

Resting Membrane Potential Potassium Channels Resting Membrane Potential + Effect of external K concentration Deporlarization

Resting Membrane Potential Potassium Channels Resting Membrane Potential + Protection by blood-brain barrier Protection by astrocytes via spatial buffering

Resting Membrane Potential Sodium Channels Resting Membrane Potential + Effect of external Na concentration

Resting Membrane Potential Review Resting Membrane Potential What two functions do proteins in the neuronal membrane perform to establish and maintain the resting membrane potential? On which side of the neuronal membrane are Na ions more abundant? When the membrane is at the K equilibrium potential, in which direction (in or out) is there a net movement of K ? + + +

Resting Membrane Potential Review Resting Membrane Potential There is a much greater K concentration inside the cell than outside. Why, then , is the resting membrane potential negative? When the brain is deprived of oxygen, the mitochondia within neurons cease producing ATP. What effect would this have on the resting membrane potential? +

Neuroscience Chapter 4: The Action Potential 高毓儒 Institute of Physiology, School of Medicine National Yang-Ming University 2826-7086 yrkou@ym.edu.tw

Outline Introduction Properties of the action potential The action potential – in theory The action potential – in reality Action potential conduction Action potential, axons, and dendrites Review

Action potential vs. electricity Introduction Action potential vs. electricity Electrical charge of ions vs. generator Non-degraded vs. degraded conduction All-or-none vs. adjustable characteristic Encoding by frequency and pattern vs. magnitude of electrical power

Measurement AP-Properties

The Up and Down AP-Properties

Generation AP-Properties

Generation AP-Properties Concept of threshold Concept of all-or-none

AP-Properties Generation Absolute refractory period Relative refractory period

Current and Conductance AP-in Theory A simplified model at resting state (0 - 80 mV)

Current and Conductance AP-in Theory A simplified model - upon stimulation (-80 – 62 mV)

Current and Conductance AP-in Theory A simplified model upon stimulation (62 - -80 mV)

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Structure – 4 domains

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Structure – 6 helices for each domain

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Structure – domains for specificities

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Depolarization and pore opening

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Pore selectivity

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Patch-clamp technique

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Functional properties

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Functional properties

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Characteristics Open with little delay. Stay open for only 1 ms and then close (inactivate). Cannot be opened again by depolarization until the membrane potential returns to a negative value near threshold. The overshoot is limited by inactivation.

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Reminders Opining a single channel does not result in action potential. The membrane of axon contains thousands of Na channel per m . Concerted action within 1 ms explains the rapidly rising phase of action potential. Inactivation of Na channel accounts for the absolute refractory period. + 2 +

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Toxins Effect of TTX and Saxitoxin – channel blocker

Voltage-Gated Na Channel + Voltage-Gated Na Channel AP-in Reality Toxins Batrachotoxin (Frog) – lower the threshold and stay open Toxins from Lilies and Buttercups

Voltage-Gated K Channel + Voltage-Gated K Channel AP-in Reality Repolarization + Inactivation of Na channels (the 1st factor) A transient increase in K conductance Also open in response to depolarization with 1 ms delay - delay rectifiers (the 2nd factor) Na -K pump working in the background at all time (the 3rd factor) + + +

Overall Changes in Ionic Currents AP-in Reality

Overall Changes in Ionic Currents AP-in Reality

Overall Changes in Ionic Currents AP-in Reality

AP Conduction Propagation Characteristics Orthodromic conduction (10 m/s) Mechanism of all-or-none

AP Conduction Propagation Characteristics Only one direction and no turning back Influenced by axonal size and number of voltage-gated channels Axonal excitability Local anesthetics

Myelin and Saltatory Conduction AP Conduction Insulation by myelin

Myelin and Saltatory Conduction AP Conduction Break of insulation for ionic currents to generate AP

AP, Axons and Dendrites Difference The membrane of dendrites and cell bodies do not have enough voltage-gated sodium channels. They do not generate AP. The spike-initiation zone (axonal hillock) fires the first AP.

Difference AP, Axons and Dendrites

Action Potential Review + Define membrane potential, Na equilibrium potential. Which of these, if any, changes during the course of an action potential? What ions carry the early inward and late outward currents during the action potential? Why is the action potential referred to as “all-or- none”?

Action Potential Review + Some voltage-gated K are known as delay rectifiers. What would happen if these channels took much longer than normal to open? What parts of the cell would you see the labeling of TTX? What would be the consequence? How does action potential conduction velocity vary with axonal diameter? Why?