Chapter 9: Cell Communication

Basic Mechanisms of cell communication

Communication between cells is common in nature. Cell signalling occurs in all multicellular
organisms, providing an indispensable mechanism for cells to influence one another.

Cells can communicate through any of four basic mechanisms, depending primarily on the
distance between the signalling and responding cells. These mechanisms are:

1. Direct contact
2. Paracrine signalling
3. Endocrine signalling
4. Synaptic signalling

**Some cell can send signals to themselves, secreting signals that bind to specific receptors
on their own plasma membrane – this is called autocrine signalling

1. Direct Contact

 The surface of an eukaryotic cell is densely populated with membrane molecules

(proteins, carbohydrates and lipids) which attach to and extend outward from the
plasma membrane.
 When the cells are close to one another, some of these membrane molecules (proteins,
carbohydrates and lipids) of one cell can be recognised by receptors on the plasma
membrane of the adjacent cell
 Adjacent cells can also communicate through gap junctions
 2. Paracrine Signalling

 Signal molecules diffuse through the extracellular fluid to other cells

 These molecules can be taken up by neighbouring cells, destroyed by cellular enzymes,
or quickly removed from the extracellular fluid in some other way
 Hence, signals have short-lived, local effects
 Affects cells of immediate vicinity
 For example: signalling between immune cells in vertebrates

3. Endocrine signalling

 Longer lived signal molecules

 Signal molecules may enter the circulatory system and travel widely throughout the
body
 Affect cells very distant from the releasing cell
 For example: hormones
 4. Synaptic signalling

 In animals, the cells of the nervous system provide rapid communication with distant
cells
 Mediated by neurotransmitters in chemical synapse
 The long fibre-like extensions of the nerve cells release neurotransmitters from their tips
very close to target cells
 Association of a neuron and its target cell – chemical synapse
 Example: Between neuron and its target cells

Ligand & Receptors

Communication between cells requires

1. Ligand – signalling molecule
2. Receptor protein – molecule to which the ligand binds

 The interaction of these two components initiates the process of signal transduction,
which converts the information in the external signal (ligand) into a cellular response. 
 Signal transduction refers to events within the cell that occur in response to a signal
(ligand).
 Signal transduction pathway – Signal transduction pathways are a series of relay
molecules that amplify the incoming signal by a phosphorylation cascade to ultimately
generate a precise and appropriate cellular response.

**Smart book: One important class of cytoplasmic kinases are Mitogen-activated protein
(MAP) kinases. A Mitogen is a chemical that stimulates cell division by activating the
normal pathways that control division. The MAP Kinases are activated by a signalling
module called a phosphorylation cascade or a kinase cascade.

3 stages of cell signalling

1. Reception
 Signalling molecule binds to a receptor protein
2. (Signal) Transduction
  Signal is passed through a series of relay molecules (signal transduction pathway)
3. Response
 Target molecule is activated  specific cellular response

Major types of ligands

 Hydrophobic ligands – can easily cross the cell membrane
 Hydrophilic ligands – cannot easily cross the cell membrane

Examples of signal molecules: Peptides, large proteins, individual amino acids, nucleotides,
steroids and other lipids. Dissolved gases such as Nitric oxide (NO)

Major types of receptors

 Intracellular – For hydrophobic ligands which can cross the plasma membrane
 E.g. Steroid hormone receptor
 Nitric oxide receptor
 Plasma membrane (cell surface) – For hydrophilic ligands which cannot cross the
membrane
 E.g. Channel-linked receptors
 Enzymatic receptors
 G protein-coupled receptors

Phosphorylation of Proteins

Phosphorylation
 Addition of phosphate group to a molecule
 A cell’s response to a signal often involves activating or inactivating protein
 Phosphorylation is a common way to change activity of a protein
 Protein kinase (KINASES)– enzymes that phosphorylate proteins (& activate them)
 Phosphatase –enzymes that dephosphorylates proteins (& deactivate them)
 The addition or removal of a phosphate group can expose or hide potential binding sites
in proteins or change protein activity
The enzymes that add phosphate groups are called kinases. These form two classes,
either serine–threonine kinases or tyrosine kinases, depending on the amino acid the
phosphate is added to. The action of kinases is reversed by phosphatase enzyme.

Serine–threonine kinases – Kinase enzymes that adds a phosphate group to the serine or
threonine amino acid residue

Tyrosine kinases – Kinase enzymes that adds a phosphate group to the tyrosine amino acid
residue.
Cell surface receptors
These molecules can directly convert extracellular signals into intracellular signals.

Channel-linked receptors

 Chemically gated ion channels that allow passage of ions

 The channel only opens when the chemical (ligand) bind to it
 There are gated channels for sodium, potassium, calcium and chloride ions
 For example: acetylcholine receptor on muscle cell membrane is a channel-linked
receptor for sodium ion
 When the receptor binds to acetylcholine, the channel opens, allowing Na + to flow
into the muscle cell. This is a critical step linking the signal from a motor neuron to
muscle cell contraction

Enzymatic Receptors

 Receptors that also act as an enzyme

 The enzyme activity of the receptor is activated when bound by hydrophilic ligand
 Most of them are protein kinases E.g. RTK

Receptor Tyrosine Kinases (RTK)

 A large class of membrane receptors that recognise hydrophilic ligands

 A kind of transmembrane enzyme receptor
 Enzyme that adds a phosphate group to the tyrosine amino acid residue of a protein
 Mainly influence the cell cycle, cell migration, cell metabolism and cell proliferation
 Made up of 3 domains:
 Extracellular ligand binding domain
 Signal transmembrane domain
 Intercellular kinase domain

Activation of Receptor Tyrosine Kinase

 On ligand binding, 2 of these receptor-ligand complexes associate together and

phosphorylate each other (across each other, each TYR is phosphorylated), a process
called autophosphorylation
 Forms a dimer, (from 2 monomers) AKA dimerization
 The autophosphorylation event transmits the extracellular signal across the membrane
 Response proteins bind to phosphotyrosine on receptors
 Phosphorylation of response proteins by activated kinase domain
 2 different cells can have the same receptor yet a different response, depending on what
response proteins are present in the cytoplasm
 2 diff cells can also have different responses due to a difference of receptors for the
same ligand
Step 1: Step 2: Step 3:
Ligand binds to receptor 2 enzyme receptors Response proteins bind to
associate and phosphotyrosine on receptor (left).
phosphorylate each other Receptor can phosphorylate other
response proteins (right)
RTK Summary

Structure
RTK is a type of transmembrane receptor
that recognizes hydrophilic ligands
Made up of 3 domains:
i. Extracellular ligand binding domains
ii. Single transmembrane domain
iii. Intracellular kinase domain (enzyme)
Function
The receptor itself is an enzyme, which
adds a phosphate group to the tyrosine
(amino acid) residue of a protein. Hence, its
name, tyrosine kinase.
Mainly influences cell cycle, cell migration,
cell metabolism and cell proliferation

** Alterations in the structure and function of receptor tyrosine kinases often leads to the
development of cancer in humans and other animals.

FROM SMART BOOK:

RTKs are inactivated by internalization. It is important that signalling pathways are not
continuously active. RTKs are inactivated by two basic mechanisms: dephosphorylation and
internalization. Internalization is by endocytosis with the receptor taken up in a vesicle
where it can be recycled or degraded.

Insulin receptor (An example of RTK)

**The hormone, insulin, is important in maintaining a constant level of blood glucose. It acts
to lower blood glucose by signalling through an RTK.

 A type of receptor tyrosine kinase

 Binding of insulin on the insulin receptor leads to auto-phosphorylation of the
receptor
 Insulin response protein binds to the phosphorylated receptor and passes the signal
on to another response protein that activates glycogen synthase, which converts
glucose to glycogen.
 Other insulin response proteins will:
o Inhibit the production of enzymes involved in making glucose
o Increase the number of glucose transporter proteins in the plasma
membrane
 Together, these responses act to lower blood glucose
G Protein-coupled receptors (GPCR)

 Single largest category of receptor type in animal cells

 Receptors that act by coupling with a G protein
 Acts indirectly on enzymes or ion channels in the plasma membrane with the aid of G-
protein
 Has seven transmembrane domains that anchor the receptors in the membrane (AKA 7
α helixes side by side)
 ~800 genes in human encodes for GPCR, with half of them encode for odorant receptors
involved in taste and smell

G protein

 It is a transmembrane protein
 All G proteins are active when bound to GTP (guanosine triphosphate) and inactive
when bound to GDP (guanosine diphosphate)
 Provide the link between the receptor and effector proteins that produce cellular
responses
 Made up of 3 subunits, α, β, γ, also called heterotrimeric G proteins

G protein signalling mechanism steps

 G proteins are active when bound to GTP and inactive when bound to GDP
 Upon binding of ligand on its associated receptor, G protein exchanges GDP for GTP
and is activated
 G protein dissociates into two parts consisting of the Gα subunit bound to GTP, and
the Gβγ subunit (Gα usually for enzymes or Gβγ usually for ion channels)
 The GTP bound Gα subunit then binds and activates effector proteins which are
usually enzymes (such as adenylyl cyclase)
 Thus, provides the link between the receptor and effector proteins that produce
cellular responses
 The activated effector protein may act directly on cellular proteins or produce a
second messenger (such as cAMP) to cause a cellular response.
 The hydrolysis of bound GTP to GDP by Gα causes reassociation of the G protein and
restores the inactive state
Summary for G Protein-coupled receptors (GPCR)

Structure Function
G protein is made up of 3 subunits, α,β,γ, G proteins provides the link between the
therefore it’s also called heterotrimeric G receptor and effector proteins that produce
protein. cellular responses

There are 7 transmembrane domains that There are extracellular receptors that act by
anchor the receptor in the membrane. coupling with a G protein.

Single largest category of receptor type in Acts indirectly on enzymes or ion channels
animal cells. in the plasma membrane with the aid of G
proteins.

~800 genes in human encodes for GPCR,

with half of them encode for odorant
receptors involved in taste and smell
Effector protein
 Usually enzymes, which may:
1. Act directly on cellular proteins by phosphorylation
2. Produce a second messenger to initiate a signal transduction pathway

 Two common effector proteins which produce 2nd messenger:

1. Adenylyl cyclase (2nd messenger: cyclic AMP) (RECEPTOR IS GPCR)
2. Phospholipase C (2nd messenger: IP3 and DAG)

Adenylyl cyclase  forms cyclic AMP (cAMP)

Production of second messengers:

 Second messengers are signalling molecules produced within the cell
 The nucleotide ATP is converted by the enzyme adenylyl cyclase into cyclic AMP,
or cAMP, and pyrophosphate (PPi) in the Adenylyl cyclase enzyme
Cyclic AMP (cAMP)

 Second messenger of the effector protein adenylyl cyclase

 The nucleotide ATP is converted by the enzyme adenylyl cyclase into cyclic AMP,
or cAMP, and pyrophosphate (PPi) in the Adenylyl cyclase enzyme
 cAMP binds to and activates the enzyme protein kinase A (PKA), which adds
phosphates to specific proteins in the cell

Summary

Chemically gated ion Enzymatic receptors G Protein-coupled

channels
Chemically gated ion
channels form a pore in the
plasma membrane that can
be opened or closed by
chemical signals. They are
usually selective, allowing
the passage of only one
type of ion.
receptors
Enzymatic receptors bind to G protein-coupled receptors
ligands on the extracellular (GPCRs) bind to ligands
surface. A catalytic region outside the cell and to G
on their cytoplasmic portion proteins inside the cell. The
transmits the signal across G protein then activates an
the membrane by acting as enzyme or ion channel,
an enzyme in the cytoplasm. transmitting signals from
the cell's surface to its
interior.
Intracellular receptor
Steroid Hormone Receptors

 Intracellular receptor present in the cytoplasm of the cell

 Ligands are steroid hormones: cortisol, oestrogen, progesterone, testosterone
 Travel from endocrine cells  target cells through the bloodstream (endocrine
signalling)
 All are lipid-soluble (hydrophobic)
 Steroid hormones are non-polar and can readily diffuse across the plasma membrane
 Three functional domains in a steroid hormone receptor:
1. A hormone binding domain
2. A DNA binding domain
3. A domain that can interact with coactivators to affect the level of gene transcription

 Activation of Steroid Hormone Receptor

1. Steroid hormone receptors are inactive before binding of hormones and cannot bind
onto DNA
2. Upon binding of hormones, inhibitor proteins will be released from the DNA binding
domain
3. Formation of steroid-receptor complex also leads to a shift from the cytoplasm to
the nucleus
4. In the nucleus, the DNA binding domain of the receptor attach to specific nucleotide
sequences on the DNA, at sites near the genes they regulate
5. The primary function (or the cellular response) is the regulation of gene expression
(by activating or inhibiting gene transcription)
Structure
Steroid hormone receptors have 3 functional
domains:
 A hormone binding domain
 A DNA binding domain
 A domain that can interact with
coactivators to affect the level of gene
transcription
They (ligands) are non-polar and can readily
diffuse across the plasma membrane
Properties (of receptor)
The steroid hormone receptor is a kind of
intracellular receptor present in the
cytoplasm
Their ligands are steroid hormones like:
Cortisol, oestrogen, progesterone,
testosterone
They are inactive before binding to hormones
(and this, cannot bind to DNA)

NOTE
Hydrophilic steroids Hydrophobic steroids
 Epinephrine  Cortisol
 Insulin  Oestrogen
 Progesterone
 Testosterone
Nitric oxide receptor

 A type of intracellular receptor found in the cytoplasm

 Generated by endothelial cells of the blood vessels
 A receptor that act as an enzyme: Guanylyl cyclase
 Nitric oxide, a small gas molecule, is able to diffuse readily into the cell
 Nitric oxide binds to and activates guanylyl cyclase, leading to the production of cyclic
guanosine monophosphate (cGMP)
 The effect is to cause relaxation of smooth muscle cells, resulting in dilation of blood
vessel and increased blood flow

Medicines related to the NO receptor

Nitroglycerin
 A drug used to treat angina
 Converted by cells to NO, which then act to relax the blood vessels, relieve the
symptoms of angina
 NO serves as a ligand for the nitric oxide receptor

Viagra
 Viagra work by inhibiting the enzyme cGMP phosphodiesterase which causes the
breakdown of cGMP
 Thus, cGMP remains high in the cell and allows relaxation of smooth muscle in
erectile tissue, thereby increasing blood flow
 Viagra does not bind onto any intracellular receptor, but helps to maintain the effect
produced by the activated nitric oxide receptor (dilation of blood vessel).