MEMBRANE PHYSIOLOGY

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 Objectives
At the end of this course students are expected
to:
Write components of cell membrane and their
functions
Understand cell signaling by electrical excitation

Define what membrane potential mean

List different ion channels and their functions

2
 Contd
Differentiate action potential and graded potential

Define synapse and its function

Compare and contrast electrical and chemical

synapses
Discuss cell communication

Explain cellular transduction process

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 what is cell?
The cell is the fundamental structural and functional
working unit of all organisms
It possesses and exhibits the basic properties of living
matter.
Cell is the smallest living unit and it is microscopic.

Cells are structural & functional unit in our body.

Human body is assembled of eukaryotic cells.

There are 75-100trillion cells in our body

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 The three fundamental cell theories are:-

1. Cells come from pre-existing cells.

2. A cell is a fundamental unit of life. (i.e. all

living things are made up of cells.)

3. Cell is capable of maintaining its existence

(metabolize, grow & reproduce on its own).

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 Basic cell functions:-
Obtaining food (nutrients) & O2 from nearby envt .

Performing various metabolic energy production

Elimination of waste products (CO2 & others)

Synthesis of materials for cellular structure, growth,&

carrying out cellular functions
Sensitivity & responsiveness to changes in its envt

Control of material exchanges b/n cell & envt.

Moving materials within the cell in carrying out cellular

activities.
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Eukaryotic Cell Structure and function
3 main parts of the cells are:
Nucleus the largest organelle in the cell

Cytoplasm -the region b/n the plasma membrane &

nucleus.
Filled with intracellular fluid (cytosol).
Most organelles are suspended in cytoplasm
Plasma membrane- the outer covering of the cells.

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Cell structure and function

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 Cytoplasm
Material enclosed by plasma membrane

Is a watery solution of minerals, gases, organic molecules, and cell

organelles that is found between the cell membrane and the
nucleus.
It is a fluid matrix, the cytosol, which consists of 80% to 90%
water, salts, organic molecules and many enzymes that catalyze
reactions.
Cytosol is the water portion of cytoplasm, and many chemical
reactions take place within it.

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Cell Organelles
Are intracellular structures, often bounded by their
own membranes, that have specific functions in
cellular metabolism
Highly organized structures
are basic machinery found within cells.

are responsible for the functioning of the cell.

perform essential activities for survival of cell.

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Nucleus

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 Endoplasmic Reticulum (ER)
-Network of membranes made up of tubes,
sacs & chambers called cisternae
Attached to the nuclear envelope
-2 forms:

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 Contd
a. Rough endoplasmic reticulum (RER)
-studded with ribosomes
-ribosomes synthesize proteins and feed
them into RER cisternae to be modified(e.g. +carbs
= glycoprotein)
-modified proteins put into transport vesicles to go
to Golgi
-these proteins for exocytosis or use in membrane
b. Smooth endoplasmic reticulum (SER)
-tubular membranes
-no ribosomes
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 Contd
Functions of SER:
1. lipid metabolism (synthesis, breakdown,transport)
2. synthesis of steroid hormones
3. detoxification of drugs
4. breakdown of glycogen to glucose
5. store ions (e.g. Ca2+)

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 Endoplasmic reticulum.

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Golgi apparatus
Is a set of stacked membranes

near nucleus but not attached

functions to modify, concentrate, & sort export proteins

It modify proteins to the final stage of production

adds sugar molecules to side groups, protects proteins

from breakdown
Packages proteins into vesicles for secretion or internal
use
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Contd

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18
 Cytoskeleton structure that gives mechanical
support to the cell
helps cell to maintain its shape

Enables a cell to change shape in an adaptive

manner
help for cell motility:
organelle movement,
muscle contraction, and
Plays a regulatory role by transmitting signals
from cell's surface to its interior.
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 cytoskeleton

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Plasma Membrane

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Cell membrane/plasma membrane
Is very thin structure that covers the outer surface of a cell with about 7-10 nm thick.

It separate cellular content from environment(It forms boundary of the cell).

It control movement of material into and out of the cell.

It is lipid bilayer (made of phospholipids arranged in double layer).

The phospholipids has both hydrophobic and hydrophilic regions.

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 Contd

Thus phospholipids in cell membrane are held together by

hydrophobic interactions
The lipid layer in the middle of the membrane is impermeable
to the usual water-soluble substances, such as ions, glucose,
and urea.
Conversely, fat-soluble substances, such as oxygen, carbon
dioxide, and alcohol, can penetrate this portion of the
membrane with ease

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 The phospholipids in the cell form a bilayer that acts as a semi
permeable boundary between the cell membrane and its external
environment
It is composed almost entirely of proteins and lipids
Membrane composition is 55% proteins; 25% phospholipids;
13% cholesterol; 4% other lipids and 3% carbohydrates.

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 Membrane Functions
Protection(Support & retain the cytoplasm)

Cell to cell communication(Communication via receptors)

Selectively permeable - controls what goes in and out of cell or

organelle
Respond to environment

Recognition

Signal transduction interface

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 Components of the cell membrane
Contains lipids, proteins and carbohydrates

Lipids

Phospholipids -self assemble into bilayer

Cholesterol-resist osmotic lysis

Proteins

Integral -span width of membrane

Peripheral-adhere to inner or outer surface

Carbohydrates linked to other molecules

as glycolipids and glycoproteins

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27
Contd

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 Cell Membrane Structure
1. Lipids
Phospholipids:
Hydrophilic head (likes
water)
Hydrophobic tails
(cannot be in contact with
water)
Cholesterol:
o Stiffens membranes
o Can move in any dimension
through membrane
o contributes to both the
fluidity and the stability of
the membrane.

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30
Cholesterol molecules are
tucked in between the
phospholipids molecules,
where they prevent the fatty
acid chains from packing
together and crystallizing,

Through their spatial

relationship with
phospholipid molecules,
cholesterol molecules also
help stabilize the
phospholipids position

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 Contd

The lipid bilayer serves three important functions:

1. It forms the basic structure of the membrane.

The phospholipids can be visualized as the pickets
that form the fence "around the cell.

2. Its hydrophobic interior serves as a barrier to passage of

water-soluble substances between the ICF and ECF.

3. It is responsible for the fluidity of the membrane

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 2. Proteins: mass of membrane
a. Peripheral proteins:
- Adhere to inner or outer surface
Hydrophilic and readily dissociated from membrane.
Free, floating on the surface (stud the inside and the
outside of the membrane) and account for about 30% of
the membrane proteins.
Bind specific hormones and proteins on cell membrane.
They also function as enzymes.

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34
 b. Integral proteins
span width of membrane
Transmembrane proteins (trans means across).

Exist as separate globular units running through

the width of the cell membrane

Partly hydrophilic (polar and protruding to cell

surface) and partly hydrophobic (non-polar and
embedded in the lipid bilayer).

Protruding part may often carry CHO chains or

lipids attached to their tips like flags . 35
 Contd
Tightly associated with membrane and account
for about 70% of the membrane proteins.

Many of them provide structural channels (or

pores) through which water molecules and
water-soluble substances, especially ions can
diffuse in and out of the cell.

Other integral proteins act as channels,

carriers, pumps, enzymes and receptors.

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Contd

37
Function of cell membrane proteins

Transporter (Channels + Carriers)

Receptors
Enzymes
Signal Transducers
Support
Cell-to-cell recognition
Cell-to-cell junction

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3. Carbohydrates
PolysaccharidesHydrophilic
Always found on the exterior surface of cells.
Glycocalyx:
Glycoproteins = CHO + Proteins
Glycolipids = CHO + Lipids
Used for cell -to-cell recognition
These carbohydrate chains play an important role in
recognition of self and in cell-to-cell interactions.
Cells can recognize other cells of the same type and join to
form tissues
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40
Cellular Transport Function/ Membrane transport
Transport across cell membrane
Passive transport and
Active transport

Passive transport
Do not require energy
From high to low concentration
Down concentration gradient
Eg. Osmosis
Simple diffusion
Facilitated diffusion
Osmosis is net flow of water molecule from high water content
to low water content across selectively permeable membrane.

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 Passive Transport Mechanisms contd
Cell uses no energy
Molecules move randomly from an area of high concentration
to an area of low concentration (HighLow).
At equilibrium, movement is equal in both directions
Three types:
1. Simple Diffusion:
.Free movement of a substance from one part of a solution to
another occurring in both directions.
.Net movement occurs from an area of high concentration to
another area of low concentration.

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Rate of diffusion is affected by:
Viscosity of solution

Molecular weight

Concentration gradient: Difference in concentration between two

points
Permeability of the membrane / medium

Available surface area and thickness of membrane

Distance traveled across which diffusion must occur (inverse)

Solvent state (gas > liquid > semisolid)

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 2. Facilitated Diffusion
-Require no energy
Glucose
-Is carrier mediated transport molecules
- Cellular Transport From a- High
High Concentration

Cell Membrane

Low Concentration Protein

Through a Transport Protein

L channel

uses a carrier to facilitate (assist) the transfer of a particular substance

across the membrane downhill from high to low concentration .
Go to
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Section:
Facilitated diffusion includes contd
i. carrier-mediated transport- uniport and symport
ii. carrier-mediated exchange- anti-port
iii. ion channels and channels for other small molecules

Uniport Symport Antiport

Classes of A A B A
carrier
proteins

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 3. Osmosis
the diffusion of water across a semi-permeable membrane

Water moves from solution with lower concentration of

osmotically active solutes
Water moves from dilute solution to concentrated solution

Osmotic potential is the total of all dissolved particles

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 Active Transport
o Active transport requires Energy.
o Movement from an area of low concentration to an area of
high concentration (Low High).
o When cells must move materials in an opposite direction -
against a concentration gradient.

- Proteins or Pumps are found in the cell membrane transport

molecules across the membrane.
o Three types
1.Protein Pumps
2.Endocytosis
3.Exocytosis
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Contd

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 Contd
Active transport
Requires the carrier to expend energy to transfer its passenger
uphill against a concentration gradient, from an area of lower
concentration to an area of higher concentration

Active transport is carrier-mediated transport that uses energy

and moves a substance against its concentration gradient

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 Contd
Active transport comes in two forms.

In primary active transport,

Energy is directly required to move a substance
against its concentration gradient

The carrier splits ATP to power the transport

process

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 Contd
The most important example is a sequentially active NaK
ATPase pump (NaK pump for short) found in the plasma
membrane of all cells.
This carrier transports Na out of the cell, concentrating it in
the ECF, and picks up K from the outside, concentrating it in
the ICF .
The pump has high affinity for Na on the ICF side

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Contd

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 Contd
In secondary active transport,

energy is required in the entire process, but it is not

directly used to produce uphill movement.
the carrier does not split ATP; instead, it moves a molecule
uphill by using secondhand energy stored in the form of
an ion concentration gradient (most commonly a Na
gradient).
This ion gradient is built up by primary active transport of
the ion by a different carrier.

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The NaK pump plays three important roles:
1. It establishes Na and K concentration gradients across the
plasma membrane of all cells;
these gradients are critically important in the ability of nerve
and muscle cells to generate electrical signals essential to their
functioning
2. It helps regulate cell volume by controlling the
concentrations
of solutes inside the cell and thus minimizing osmotic effects
that would induce swelling or shrinking of the cell.
3. The energy used to run the NaK pump also indirectly
serves as the energy source for secondary active transport

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 Membrane transport of macromolecules & particles
These large particles are transferred between the ICF and ECF

by being wrapped in a membrane-enclosed vesicle, a process

known as vesicular transport.
Vesicular transport
requires energy expenditure by the cell,

Is an active method of membrane transport.

Energy is needed to accomplish vesicle formation and vesicle movement

within the cell.

Transport into the cell in this manner is termed endocytosis,

whereas transport out of the cell is called exocytosis

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 Endocytosis
- cell takes in large particles by engulfing them
1. Phagocytosis - "cell eating" - extensions off cytoplasm
surround a particle and package it within a food vacuole and
then the cell engulfs it. Ex. Amoebas use this process.
2. Pinocytosis cell drinking the process of taking up liquid
from the surrounding environment. Tiny pockets form along
the membrane, fill with liquid, and pinch off.

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Exocytosis
cell gets rid of particles, opposite of endocytosis
remember the vesicles created by the Golgi Body.
These are removed from the cell by exocytosis.

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Contd

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 Cell signaling(control of cell function)
Terminology

Ion
Atom / molecule that have an electrical charge.

Anion

Negatively charged ion (e.g., Cl ).

Cation
Positively charged ion (e.g., Na+, K+, Ca2+).

Influx of ions
Flow of ions into the cell (ECF to ICF).

Efflux of ions
Flow of ions out of the cell (ICF to ECF).
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 Cell signaling by electrical excitation
Membrane Potential
Electrical energy difference between the inside and outside of the cell.

Separation of opposite charges across the plasma membrane

Thus ICE is relatively -ve while ECE is relatively +ve

Em = Vin Vout, where

Vin = Potential on the inside of the cell

Vout = Potential on the outside
Em = Membrane potential (mV)

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 All cells have membrane potentials.

Membrane potential charge separation across the

membrane.

Any change of a membranes permeability of ions

causes a change in Em.

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Resting Membrane Potential
Steady transmembrane potential of a cell that is not producing
an electrical signal.
No net flow of ions across the plasma membrane.
(No net inward current)
Always negative in nerve and muscle cells.
Magnitude is + for individual cell types.
o Nerve, cardiac and skeletal muscle: -55 to -90mV
o Smooth muscle: -55 to -30mV

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 Inexcitable cells have RMP.

RMP is necessary for the cell to fire an action potential.

Resting membrane potential is nearly equals to that of EK

NB. Excitable cells (nerve cells and muscle cell) have the
ability to produce rapid, transient changes in their
membrane potential when excited.

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64
65
Determinants: Origins of Em
Passive determinants
Active determinant

Passive Determinants
A. Biochemical nature of plasma membrane of the cell.
Lipid bilayer (7nm = 60): Selective permeability
Extracellular: +VE
Intracellular: - VE

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 B. Asymmetrical/Unequal distribution of ions across the
membrane

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 Concentration of ions
Electrostatic
Inside Outside [ ] gradient pressure

Sodium (Na+) 12mM 145mM into cell into cell

Potassium (K+) 150mM 5mM out of cell into cell

Chloride (Cl-) 9mM 125mM in out

Calcium (Ca2+) 10-4mM 2.5mM into cell into cell

Organic anions: Fixed anions (Proteins, nucleotides, polyphosphates)

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C. Leakage (Leak, non-gated, passive, resting) channels

Leak K+ channels, leak Na+ channels, leak Cl- channels

Leakage K+ channels are open at resting potential more than Na+, Cl-

Resting membrane potential is nearly equals to that of the EK.

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D. Diffusional force

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Nernst Equation/Nernst Potential
Used to calculate the equilibrium potential for a given ion with
differing concentrations across a membrane
Equilibrium potential is a measure of membrane potential

i. Conc. of the ion inside and outside

ii. Temperature of the solution

iii. The valence of the ion

iv. The amount of work required to separate a given quantity

of
charge.
Ex = RT ln [X]o
(mV) zF [X]I 71
Where
R = gas constant = 8.315jk-1mol-1
T = TKelvin = 271.16 + TCelcius

F = Faraday's constant = 96, 485 Cmol-1

z = Valence of the ion (+1, -1, +2)
[X]o = Concentration of the ion outside the cell
[X]i = Concentration of the ion inside the cell

Ex = 61 log10 [X]o
[X]i
Z
NB. Nernst Equation predicts Equilibrium Potential (Eion).
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Goldman-Hodgkin-Katz Equation
Used to calculate membrane potential
Considers the relative permeabilities and concentration gradients of
all permeable ions

Em = RT ln PK[K+]o + PNa[Na+]o +PCl[Cl-]i

F PK[K+]i + PNa [Na+]i + PCl[Cl-]o

(Permeability = PK: PNa: PCl, 1.00: 0.04: 0.45)

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Goldman-Hodgkin-Katz Equation

1. The contribution of any ion to the Em is determined by

the membranes permeability to that particular ion.

2. The higher the permeability of the membrane to one

ion relative to the others, the more that ion will contribute
to the Em.

3. The contribution of the impermeable ion to the Em will

be zero.
NB. GHK = predicts Resting Membrane of a cell.

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Active Determinant

Na+-K+-ATPase (Na+-K+ pump)

A carrier molecule uses the membrane-bound ATPase.

Primary active transport process (consumes ATP, pumps against
conc. or electrical gradient).
Operates as antiporter (coupled transporter):
Pumping 3Na+ out of the cell
Pumping 2K+ in .
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Functions
i. Maintenance of gradient of Na+ and K+ across the cell
membrane
Controls cell volume ( Na+ regulating osmotic forces)

ii. Control of membrane potential and excitability.

Na+K+ATPase
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Na+K+ATPase
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 Ion channels
Electrical signals are produced by changes in ion movement
across the plasma membrane.

The water-soluble ions responsible for carrying charge cannot

penetrate the plasma membranes lipid bilayer,

these charges can cross the membrane only through channels

specific for them or by carrier-mediated transport.

Membrane channels may be either leak channels or gated channels

78
leak channels
which are open all the time

permit unregulated leakage of their specific ion across the

membrane through the channels.

Gated channels

Are complexes membrane protein.

These channels are normally closed,
but open in response to appropriate signal (stimulus)
Then allow specific ions to flow into or out of the cell

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 Gated channels contd

Have gates that can be open or closed, permitting

ion passage through the channels when open and
preventing ion passage through the channels
when closed.
Gate opening and closing results from a change
in the conformation (shape) of the protein that
forms the gated channel.
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 There are four kinds of gated channels,
depending on the factor that causes the change in channel
conformation:

(1) voltage-gated channels

(.These channels are regulated by the membrane potential.

(.open or close in response to changes in membrane potential;

() The most prominent of these channels is the voltage-gated Na+

channel.
() Its opening underlies the initiation of an action potential

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 Contd
(2) chemically gated channels/ Ligand-gated ion channels:
change conformation in response to binding of a specific
extracellular chemical messenger to a surface membrane
receptor;

Are regulated by a specific molecule that binds to the ion

channel.

Postsynaptic neurotransmitter receptors are ligand-gated ion

channels
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 Contd
(3) mechanically gated ion channels
respond to stretching or other mechanical deformation
Touch receptors in the skin and
Receptor cells in the inner ear are examples of mechanically gated ion
channels.

These channels open through the mechanical deflection that pries

or pulls the channel open

(4) thermally gated channels

respond to local changes in temperature (heat or cold).

The channel protein acts as a thermometer, and a change in

temperature opens the channel pore
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84
 Contd

Passive Ion Channels

Found on dendrites, cell body, and axon.

Chemically-gated Ion Channels

Found on dendrites & cell body.

Voltage-gated Ion Channels

Found on axon hillock, unmyelinated axons
and at nodes of Ranvier on myelinated
axons.

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Contd

86
 Em: initiate electrical signaling in excitable
cells
Basis of signaling in the NS.

Types: 1. Graded potentials

2. Action potentials

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1.Graded potentials

a. Def.:- local changes in membrane potential (Em) in

either depolarizing or hyperpolarizing direction.

.Are local changes in membrane potential that occur in

varying grades or degrees of magnitude or strength.

.which serve as short-distance signals

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 Graded potential contd
It is local electrical disturbance
Propagate like wave in all direction

Its propagation is decreasing (as it go away from point of

origin its amplitude )
Its amplitude depend on strength of stimulus

Strong stimulus generated large graded potential that can

propagate longer distance

Occurs in dendrite, cell body or motor end plate

b/c these parts lacks voltage gated ion channel
If it reaches threshold potential it generate action potential.
89
 Sub-threshold stimulus do not generate action potential (weak
stimulus < threshold not generate action potential).

Threshold is minimum required potential to generate action

potential

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 Weak stimulus cause opening of few ion
channels.
Influx of few ions- little disturbance- easily
disappear-with out causing action potential.

Strong stimulus cause opening of many ion

channels.

Influx of many ions- large disturbance-not easily

disappear-propagate longer distance-if it reaches
threshold point initiate action potential.
91
Subthreshold and suprathreshold graded potentials in a neuron.
In (a), the graded potential is below the threshold value (T) of *55 mV as it
reaches the trigger zone.
In (b), the graded potential is above the threshold value when it reaches the trigger
zone. 92
Summary of GP
Features:
1. Depolarizing or hyperpolarizing
2. Variable in amplitude and duration
(AM)
3. Conducted decrementally
4. Can be summed
5. Has no threshold
6. Has no refractory period

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Types:

Receptor Potentials/Generator Potentials

Graded Potentials Pacemaker Potentials

Excitatory Postsynaptic Potentials/EPSP

Synaptic Potentials
Inhibitory Postsynaptic Potentials/IPSP

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Mechanism Stimulus (physical, mechanical, chemical, electrical)
of signaling:
Sensory receptors

Transform stimulus energy/Transduction

Ion channels open

Inward flow of current

Depolarization Em

Receptor potential/Generator potential

Action Potential

CNS ... RESPONSE. 95
Action Potentials

Def: rapid, transient, self-propagating electrical excitation in the

plasma membrane of excitable cells.
Genesis/Initiation: electrical perturbation Em AP.
Sequential opening of voltage-gated channels of Na+ and K+.
which signal over long distances

96
 Part I

Characteristics of AP:

1. All-or-none phenomenon.
Always be full sized.
It will not get lost along the way.
Rapid and reliable information.
2. Has threshold.
3. Amplitude and duration is
4. Always depolarizing.
5. Has refractory period.
6. Nondecremental.

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 Part I

98
 Contd
All or none law

The principle that the strength by which a nerve

or muscle fiber responds to a stimulus is not
dependent on the strength of the stimulus

If the stimulus is any strength above threshold,

the nerve or muscle fiber will give a complete
response or otherwise no response at all

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100
 contd
Physiological basis of AP
When the threshold level is reached
Voltage-gated Na+ channels open up
Since Na conc. outside is more than the inside
Na influx will occur
Positive ion coming inside increases the positivity of the
membrane potential and causes depolarization
When it reaches +30, Na+ channels closes
Then Voltage-gated K+ channels open up
K+ efflux occurs
Positive ion leaving the inside causes more negativity
inside
the membrane
Repolarization occurs
101
 Contd
Since Na+ has come in and K+ has gone out

Membrane has become negative

But ionic distribution has become unequal

Na+/K+ pump restores Na+ and K+ conc.

By pumping 3 Na+ ions outward and 2+ K ions

inward

102
 Stages of Action Potential.
Stages of AP are
Resting stage
Depolarization stage
Repolariztion stage
Hyperpolarization stage

103
 Events in different stages of action potential.

104
Phases of an AP and Inward and outward currents
105
Phases and Ionic Basis of Action Potential
1.Threshold Potential

Minimum value of Em at which an action potential will occur .

Em is reduced to a critical level excitable cells undergo rapid

depolarization.

Initiated by rapid opening of fast Na+ channels.

AP occurs only when the NET movement of positive charge is

inward (gNa+ > gK+ or Na+ influx > K+ efflux).

106
 Magnitude is 10-20mV (-70mV -55mV).

Strength of stimuli

Subthreshold
Threshold Stimuli

107
 Suprathreshold stimuli

108
2. Depolarization Phase/ upstroke

gNa+ flow of Na+ into the cell

m, h gates opened.

109
Sodium channels exert positive feedback on membrane potential.
110
3. Overshoot/peak of the action potential

i. Portion of the AP during which the membrane is positive.

ii. Magnitude: 30 to 40mV
iii. Approaching ENa+

Potassium channels exert negative

111
feedback.
4. Repolarization/Downstroke

i. Rapid return of the membrane towards its RMP.

ii. Reasons:

a. Time-limited nature of Na+ permeability

(gNa+ is short-lived)

b. Closure of h-gate of Na+ Na+ inactivation

c. gK+ (delayed opening of K+ channels, n-gates open, activated)

112
5. Afterpotentials/undershoot
Membrane becomes more negative than its RMP at the end of
the
action potential.

5.1. Hyperpolarization afterpotential (-70mV -72/-73mV, 40ms)

n gates opened K+ out of the cell inside negativity
excitability.

113
 Refractoriness/Refractory period

i. Def. an interval during which it is more difficult to elicit an AP.

( voltage and time-dependent nature of gating particles) .

ii. Types:
a. Absolute refractory period
b. Relative refractory period

114
a. Absolute Refractory Period:
Another AP can not be elicited, regardless of the strength of the
stimulus.
Begins at the start of the upstroke and extends into the downstroke.
During the upstroke m gates are opening.
During the early portion of the downstroke Na+ channels are
inactivated by h gates.
Ends when the number of inactivated Na+ channels is reduced by
repolarization.
NB. ARP Ensures ONLY one-way of propagation of APs along an
axon.

115
b. Relative Refractory Period

A second AP can be elicited if the stimulus is adequate.

Stimulus must be greater than normal (suprathreshold)

i. The Na+ channels are still inactivated.

ii. More K+ channels than normal are still open.

NB. RRP helps to limit frequency of AP

116
 Contd

Functions of refractory period

Ensures ONLY one-way of propagation of APs along
an axon.
Imposes a limit on the maximum rate a neuron can
fire.
Prevents APs from summating.

117
Refractory periods
118
119
120
Na+ channel: 2 gating particles

a. m-gate: covers the EC side of the Na+ channel.

b. h-gate: covers the IC side of the Na+ channel.
m-gate open: activation of Na+ channel
h-gate close: inactivation of Na+ channel

c. Both m and h gates must be open for Na+ to flow thru the Na+
channel.

121
122
Conformations of voltage-gated sodium channels contd

Voltage-gated Na+ channel can exist in three conformations:-

Closed but capable of opening (activation gate closed, inactivation gate
open)
Activated, or open (both gates open).
Inactivated, closed and not capable of opening (activation gate open,
inactivation gate closed) 123
Models of Gating Particles of Voltage-gated Na+ channel
124
K+ channel: ONE gating particle: n-gate

n-gate covers the IC side of the K+ channel

n-gate must be open for K+ to flow thru the K+ channel.

n-gate open: activation of the K+ channel

K+ channel does not have an inactivation gate.

125
Conformations of voltage-gated potassium channel

126
Propagation of Action Potential
Types:

i. Cable conduction/Continuous/Sweeping/conduction
Unmyelinated nerve
Speed of AP diameter of the fiber (1m = 1m/s =
slow)

127
Cable Conduction
128
ii. Saltatory Conduction
Occurs in myelinated nerve

1. Myelin sheath: covers some axon is made from cytoplasm of

glial cells:
Schwann cells PNS
Oligodendroglia CNS.
2. Nodes of Ranvier - little gaps in the myelin sheath

The electrical signal is said to jump from node to node, thus it is

called saltatory conduction
Significance:
i. Myelin sheath: high resistance + lower capacitance.

ii. increase velocity (fast, unidirectional)

129
130
131
Saltatory conduction
132
Saltatory conduction
133
Saltatory conduction
134
135
Factors affecting propagation of AP
a. Type of fiber (myelinated or non myelinated neuron)
Velocity myelination
Velocity in myelinated n > nonmyelinated nerve
b. Geometry of the fiber: diameter of axon
Larger axon conduct signal faster than smaller axon
Because there is less friction between the moving charged particles
(Na+ and K+) and sides of axon in larger axon
Velocity diameter of the fiber (SA, R)
c. Temperature-
increase temp. chemical reaction speeds up
o C rate of change of permeability
(effect on the enzymatic machinery)

136
Contd

137
 Transmission of excitation from cell-to-cell
(synapses)
Synaptic transmission
Is the transfer of signals from one cell to another.

Is communication among neurons, with muscles and glands

A neuron may terminate on one of three structures:

a muscle, a gland, or another neuron.

Therefore, depending on where a neuron terminates, it can cause

a muscle cell to contract,

a gland cell to secrete

another neuron to convey an electrical message along a nerve pathway, or some other function.

138
 Contd
Synapse
A site at which an impulse is transmitted from one cell to another

A special zone of contact at which one neuron communicates

with another
Is the functional connection between a neuron and a second cell.

In the CNS, this other cell is also a neuron.

In the PNS, the other cell may be either a neuron or an effector

cell within a muscle or gland

139
 Contd
Neuron-neuron synapses usually involve a connection between the axon
of one neuron and the dendrites, cell body, or axon of a second neuron.

These are called, respectively axodendritic, axosomatic, and axoaxonic

synapses.

In almost all synapses, transmission is in one direction onlyfrom the

axon of the first (or presynaptic) neuron to the second (or
postsynaptic) neuron.

Most commonly, the synapse occurs between the axon of the

presynaptic neuron and the dendrites or cell body of the postsynaptic
neuron.

140
Contd

141
 Contd

Synapses are typically junctions between

presynaptic and postsynaptic neurons.

There are two types of synapses:

Electrical synapses and

Chemical synapses, depending on how information

is transferred between the two neurons.

142
 Chemical synaptic transmission
There is no continuity between the cytoplasm of the
presynaptic terminal and postsynaptic neuron.
The cells are separated by synaptic clefts, which are
fluid-filled gaps (about 2050 nm).
The presynaptic and postsynaptic membranes adhere to
each other by a matrix of extracellular fibrous protein
in the synaptic cleft.
Communication is achieved via neurotransmitters
143
Contd

144
Structural components of a chemical synapse
i. Presynaptic Terminal:
Neurotransmitter(NT)synthesizing enzymes, synaptic vesicle
transporters, reuptake Transporters
Vesicles
Size
a. Small clear: Ach, glycine, GABA, glutamate
b. Small dense core vesicles: Catecholamines
c. Large dense core vesicles: Neuropeptides
Shape:
Round vesicles: excitatory transmitters
Flattened vesicles:inhibitory transmitters
145
 Synaptic transmitters

Neurotransmitters:
Are molecules released by presynaptic neurons and are the
means of communication at a chemical synapse.
Bind to neurotransmitter receptors, which can be coupled with
an ion channel (ionotropic receptors) or with

an intracellular signaling process (metabotropic receptors).

Neurotransmitters are specific for the receptor they bind to and

elicit a specific response in the postsynaptic neurons, resulting
in either an excitatory or inhibitory signal

146
Active zone: is a site of neurotransmitter release
Voltage-gated Ca2+ channels responsible for rapid NT release.
ii. Synaptic cleft:
Width: 30nm (x = 20-50nm)
Contents:
Basal lamina
Inactivating enzymatic system
iii. Postsynaptic terminal:
Transmitter-gated ion channels (ligand-gated ion channels/Ionotropic
receptors)

G-Protein coupled receptors, Gprotein-gated

ion channels/Metabotropic receptors
2nd messenger cascades (cAMP, cGMP, PLC)
147
Neurotransmitter receptors are: contd

i. Ionotropic: fast, open ionic gates and allow the flow of current thru
the postsynaptic membrane (eg., Ach).

Ionotropic Receptors
Ligand-gated Ion Channels
Directly-gated Ion Channels
148
149
ii. Metabotropic: slower, longer lasting change, affecting cellular permeability..
(using G Proteins, Ca2+, calmodulin, cAMP...) (eg., NE).

Metabotropic Receptors
G Protein-gated Ion Channels
Indirectly-gated Ion Channels

150
151
152
153
154
Types of chemical synapses
(On morphological basis)
a. Excitatory
Round synaptic vesicles
Wide synaptic cleft
Large active zone
Asymmetric postsynaptic density
Axodendritic synapse

b. Inhibitory
Flattened synaptic vesicles
Narrow synaptic cleft
Small active zone
Symmetric postsynaptic membrane
Axosomatic synapse

155
 Contd
Excitatory synapse

Presynaptic neuron neurotransmitter (Ach, glutamate, serotonin ...)

open cation channels influx of Na+ depolarization of the
postsynaptic membrane towards the threshold potential excitatory
post synaptic potential(EPSP).

Neuron action potential

Muscle contraction
Glands secretion

156
The generation of an EPSP
157
Characteristics of excitatory postsynaptic potentials(EPSPs)

Transient depolarization.
Excitatory because Em moves closer to threshold.
Increase in gNa+ .
Na+ influx causes depolarization

158
 Inhibitory synapse
Presynaptic neuron neurotransmitters (GABA, glycine ...) open Cl-
channels Cl- enters into the cell postsynaptic membrane
hyperpolarized suppress firing in postsynaptic cell IPSP.

The generation of an IPSP

159
Contd

160
Characteristics of IPSPs

Transient hyperploarizations.
Inhibitory because Em moves further away from its threshold.
Increased conductance to Cl-
Cl- influx causes hyperpolarization.
Can be produced by increased gK+ + accelerated K+ efflux or
closure of Na+ and Ca2+ channels.

161
Sequence of events at chemical synapses:
Action potential in presynaptic cell

Depolarization of plasma membrane of the presynaptic axon terminal

Entry of Ca2+ into presynaptic terminal

Release of the transmitter by the presynaptic terminal

Chemical combination of the transmitter with specific receptors in
the plasma membrane of the postsynaptic cell

Transient change in the conductance of the postsynaptic plasma membrane to specific ions.

Transient change in the Em of the postsynaptic cell

162
Sequence of events at chemical synapses
163
Sequence of events
at chemical synapses

164
165
Integration of synaptic events/
Synaptic Integration

166
Synaptic Integration

1. A central neuron receives both excitatory and inhibitory signals.

2. Excitatory and inhibitory signals are integrated into a single response

by the postsynaptic cell.

3. Excitatory synaptic action is mediated by glutamate-gated channels...

that conduct Na+ and K+.

4. Inhibitory synaptic action is usually mediated by GABA- & glycine-

gated channels that conduct Cl-.
167
5. Net effect of inputs depends on the location/proximity, size, and shape
of the synapse:
Synapses on cell bodies: inhibitory
Synapses on dendritic spines: excitatory.
Synapses on axon terminals: modulatory.
6. Net effect is sum of excitatory + inhibitory signal inputs.

168
Synaptic potentials
EPSPs and IPSPs are graded potentials.

Graded potentials can be of varying magnitude, have no

refractory period, and can be summed (added on top of one
another).
The postsynaptic neuron can be brought to threshold by either

temporal summation or

spatial summation.

169
 Synaptic Integration: Summation
Temporal
Spatial

170
Temporal summation
171
Spatial summation
172
Spatial summation

173
 If excitatory signals > inhibitory signals depolarization/excitatory.

174
 If inhibitory signals > excitatory signals
hyperpolarization/inhibitory.

175
 Action potential is initiated at the initial segment, axon hillock.

176
EPSP + IPSP = GPSP

177
178
179
 Electrical synaptic transmission
Electrical Synapses (Ephatic or electro tonic
transmission)
In ES ion channels connect the cytoplasm of the
presynaptic and postsynaptic cells
Two neurons can be coupled electrically to each
other via gap junctions

Rapid electrical signaling and information.

(In reflex reactions: escape and defensive responses)

180
 contd
Found in neuronal + non-neuronal cells.
Neuroendocrine cells of hypothalamus
(Magnocellular + Parvocellualr cells)
Lateral vestibular nucleus, inferior olive, cerebellum,
neocortex
Thalamus, striatum, hippocampus, retina, olfactory bulb
Neuroglial cells (astrocytes, Schwann cells)
Myocardial cells
Smooth muscle cells
Epithelial cells + hepatocytes
Lens
Do not generally allow inhibitory actions or long-lasting
changes in effectiveness.

181
A gap junction is a protein pore complex (connexon) that lets ions
and other small molecules move between cells . 182
 Characteristics of electrical synapses

A Em in one cell is transmitted to the other cell by the direct flow

of current (cytoplasmic bridge/gap junction between cells).

No synaptic delay (direct interactions between neighboring cells).

Allow conduction in both directions(information flow is

bidirectional).

Significance:

i. Intracellular signaling during embryonic development.

ii. Synchronization of impulses.

183
Contd

184
 Cell communication by Autacoids and Paracrine hormones
Communication between cells is largely orchestrated by
extracellular chemical messengers.
Intercellular communication can take place either

directly or

indirectly

Direct intercellular communication involves physical contact

between the interacting cells
Through gap junctions

Through transient direct linkup of surface markers

185
 Contd
Gap junctions.

Is the most close means of intercellular communication

the minute channels that bridge the cytoplasm of neighboring cells in

some types of tissues.

Through gap junctions, small ions and molecules are directly

exchanged between interacting cells without ever entering the
extracellular fluid.
186
 Contd
Transient direct linkup of surface markers.
Some cells, such as those of the immune system, have specialized
markers on the surface membrane,
that allow them to directly link with certain other cells that have
compatible markers for transient interactions.
This is how the phagocytes of the bodys defense system
specifically recognize and
selectively destroy only undesirable cells, such as cancer cells,
while leaving the bodys own healthy cells alone.

187
Contd

188
 Indirect communications
The most common means by which cells communicate with one another
is indirectly through extracellular chemical messengers or signal
molecules, of which there are four types:

Paracrines/ autocrines

neurotransmitters,

hormones, and

neurohormones.
In each case, a specific chemical messenger, the signal molecule, is
synthesized by specialized controlling cells to serve a designated purpose

189
1. Paracrine signaling
Paracrines are secreted by cells into the extracellular fluid and
affect neighboring cells of a different type(Local chemical
messengers )
They are secreted into the ECF and diffuse to adjacent cells.

Distributed by simple diffusion within interstitial fluid,

Their action is restricted to short distances.

190
 Contd

2. Autocrine signaling
Autocrines are secreted by cells into the
extracellular fluid and affect the function of the
same cells that produced them by binding to cell
surface receptors
Autocrine action: the hormone acts on the same
cell that produced it.

191
3. Endocrine signaling
Hormones are long-range chemical messengers
Secreted into blood by endocrine glands in
response to signal.
Exert effect on target cells some distance away
from release site.
To respond to a chemical signal, a target cell must
have a receptor protein for it.
Hormones reach and bind to receptors of target
cells via circulating blood.

192
4. Neurohormones
are hormones released into the blood by
neurosecretory neurons.
The neurohormones are then distributed through the
blood to distant target cells.
An example is ADH, a hormone produced by nerve cells
in brain that promotes water conservation by kidneys
during urine formation.

193
 Autacoids (Local Hormones)

-- Autocrine secretions act on the cells which secrete them

-- Paracrine secretions, secreted by some cells and act locally.

194
Contd

195
 Contd

Autacoids - local hormones

Are biological factors which act like local hormones,
have a brief duration, and act near the site of synthesis
Thus the word autacoids was used for substances that
act within restricted, local areas near their site of
synthesis,

These substances usually have a brief lifetime.

196
 contd
Heterogeneous substances have been included as
autacoids. These are:
Amine Derived
Histamine
5 Hydroxytryptamine (serotonin)
Lipid derived
Prostanoids (prostaglandins, thromboxanes)
Leukotrienes
Platelet Derived Factor
Peptide
Angiotensin
Kinins (Bradykinin, kallidin)
Vasoactive intestinal Peptide
Neurotensin
Substance P
Calcitonin Gene related Peptide 197
Histamine : is a bioactive amine , widely distributed in
animal and plant tissues.
In human body, histamine present in skin , GIT , lungs ,
CNS , CVS, basophiles.
The histamine acts as a Paracrine signal, diffusing to
capillaries in the immediate area of the injury and
making them more permeable to white blood cells and
antibodies in the plasma.

198
 Physiological role of histamine:
1- neurotransmitter in CNS.

2- Micro-circulatory regulation.

3- control sleep and alertness .

4- correlates with fetal development .

5- wounds healing.

6- Has a role in thermal and body weight regulation.

7- Gastric acid secretion.

199
Serotonin: is one of most important autacoids
Serotonin is a bioactive amine that can be synthesized by
hydroxylation of amino acid tryptophan to 5-hydroxy
tryptophan ( by enzyme = tryptophan hydroxylase) then

by enzyme aromatic amino acid decarboxylase to 5-

hydroxy tryptamine = serotonin.

200
 Contd
Physiological roles of serotonin
It acts as a neurotransmitter in the brain.

Regulation of temperature.

Pain perception .

Involved in intestinal motility .

Control of vomiting.

Control of appetite
201
 Nitric oxide (NO)
Nitric oxide [NO]:
Is a gaseous signaling molecule that readily diffuses across cell
membranes and regulates a wide range of physiologic and patho-
physiologic processes including cardiovascular, inflammation,
immune and neuronal functions.
Produced by nitric oxide synthase in the cells of many organs
from the amino acid L-arginine
In the brain NO is produced by both neuronal and endothelial cells

202
Roles of NO in the body:

Within blood vessels, it acts as a local tissue regulator that causes

the smooth muscles of those vessels to relax, so that the blood
vessels dilate. .

Within macrophages and other cells, nitric oxide helps to kill

bacteria
In addition, nitric oxide is a neurotransmitter of certain neurons in
both the PNS and CNS.
It diffuses out of the presynaptic axon and into neighboring cells by
simply passing through the lipid portion of the cell membranes.

203
 Cellular transduction process
The term signal transduction refers to the process by which
incoming signals (instructions from extracellular chemical
messengers) are conveyed into the target cell where they are
transformed into the dictated cellular response.

During signal transduction the extracellular signal is transduced,

or into a form necessary to modify intracellular activities to
accomplish the desired outcome.

204
 Contd
The extracellular signal molecule is the first messenger,

and the intracellular molecules form a second messenger

system.

In biological systems, transducers convert the message of

extracellular signal molecules into intracellular messages

that trigger a response

Membrane Proteins Facilitate Signal Transduction

205
 Contd
Binding of an extracellular messenger (first messenger)
to its matching surface membrane receptor brings about
the desired intracellular response primarily by three
general means:

(1) by opening or closing chemically gated receptor-

channels,

(2) by activating receptor-enzymes, or

(3) by activating second messenger pathways via G-

protein-coupled receptors. 206

 Contd
Almost without exception, a hormone affects its
target tissues by first forming a hormone-receptor
complex.

This alters the function of the receptor itself, and the

activated receptor initiates the hormonal effects

207
G ProteinLinked Hormone Receptors.
Many hormones activate receptors that indirectly regulate
the activity of target proteins (e.g., enzymes or ion channels)
by coupling with groups of cell membrane proteins called
heterotrimeric GTP-binding proteins (G proteins)

There are more than 1000 known G proteincoupled

receptors,
all of which have seven transmembrane segments that
loop in and out of the cell membrane.

208
 Contd
Some parts of the receptor that protrude into the cell cytoplasm are
coupled to G proteins that include three (i.e., trimeric) partsthe ,
, and subunits.

209
 The cAMP cascade & Phosphorylation

Binding of the hormones with the receptor allows coupling of

the receptor to a G protein.
If the G protein stimulates the adenylyl cyclasecAMP system,
it is called a Gs protein, denoting a stimulatory G protein.
Stimulation of adenylyl cyclase, a membrane- bound enzyme,
by the Gs protein then catalyzes the conversion of a small
amount of cytoplasmic adenosine triphosphate (ATP) into
cAMP inside the cell.
ATP cAMP + PPi
210
 Contd
This then activates cAMP-dependent protein kinase A

which phosphorylates specific proteins in the cell, triggering

biochemical reactions that ultimately lead to the cells response to the
hormone.
cAMP is called a second messenger because it is not the hormone
itself that directly intiates the intracellular changes; instead, the cAMP
serves as a second messenger to cause these effects.
Cyclic AMP activates a previously inactive enzyme in the cytoplasm
called protein kinaseA

211
 Contd

Active protein kinase catalyzes the phosphorylation of

(attachment of phosphate groups to) different proteins in the
target cells.
This causes some enzymes to become activated and others to
become inactivated.
Cyclic AMP, acting through protein kinase, thus modulates the
activity of enzymes that are already present in the target cell.
This alters the metabolism of the target tissue in a manner
characteristic of the actions of that specific hormone

212
Contd

213
Contd

214
 Inositol triphosphate and Diacyl glycerol
Some hormones activate transmembrane receptors that activate the enzyme

phospholipase C attached to the inside projections of the receptors .

This enzyme catalyzes the breakdown of some phospholipids in the cell

membrane, especially phosphatidylinositol biphosphate (PIP2), into two

different second messenger products:

inositol triphosphate (IP3) and

diacylglycerol (DAG).

The IP3 mobilizes calcium ions from mitochondria and the

endoplasmicreticulum, and

the calcium ions then have their own effects, such as smooth muscle

contraction and changes in cell secretion.

215
 Contd
Diacyl glycerol(DAG),
the other lipid second messenger,

activates the enzyme protein kinase C (PKC), which then

phosphorylates a large number of proteins, leading to the cells
response .
In addition to these effects, the lipid portion of DAG is
arachidonic acid, which is the precursor for the
prostaglandins and other local hormones that cause multiple
effects in tissues throughout the body.

216
Contd

217
 Calcium as a second messenger
Calcium enters the cell either through voltage-gated Ca2+channels or

through ligand-gated or mechanically gated channels.

Calcium can also be released from intracellular compartments by second

messengers, such as IP3.

Most intracellular Ca2+ is stored in the endoplasmic reticulum where it is

concentrated by active transport.

Release of Ca2+ into the cytosol creates a Ca2+ signal

The calcium ions combine with cytoplasmic calcium-binding proteins to

exert various effects.

218
 contd
Several types of calcium-dependent events occur in the
cell:
Ca2+ binds to the protein calmodulin, found in all cells, and alters
enzyme or transporter activity or the gating of ion channels.

Calcium binds to other regulatory proteins and alters movement

of contractile or cytoskeletal proteins such as microtubules.
For example, Ca2+ binding to the regulatory protein troponin initiates muscle
contraction in a skeletal muscle cell.

219
 Contd
Ca2+ binds to regulatory proteins to trigger exocytosis

of secretory vesicles .

Ca2+ binds directly to ion channels to alter their

gating state.

e.g. Ca2+-activated K+ channel found in nerve cells.

Ca2+ entry into a fertilized egg initiates development

of the embryo.
220
Calcium as an intracellular messenger 221
THE - END

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THANK YOU

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