BYC V ANURADHA

I YEARM.SC. HUMAN GENETICS

Cell Surface Receptors, Signalling Molecules and G-protien couple

receptors

Content

Introduction to signalling Modes

Adhesion Cell – cell interaction Cell to extracellular matrix

Signalling molecules Types Functions

Cell surface receptors Introduction Structure Functions

G-Protien couple receptors

Introduction to cell signalling

Cell signallingComplex system of communicationCellular activitiesCell functions are coordinated

Main components involved:Signalling moleculesReceptors

Cell surface receptors

Specialized proteinsIn plasma membraneIntegral proteinsHelp in communication

Signalling molecules

Chemicals and other moleculesAct as ligandsBind to receptorVary in size, shape and structureSome are capable of carrying signal over

large distances

What are the possible responses?

DifferentiationProliferationSurvivalCell specific responses

Modes of signalling

Intracrine Any hormone or

ligand acting inside a cell

For example if they act through nuclear receptors.

Modes of signalling

Autocrine signalling Signal is to the same

cell. Signalling is by

binding with a cell surface receptor.

Not a nuclear receptor.

Juxtacrine signalling Also known as

contacct dependant signalling.

Proximity between cells is mandatory for signalling to take place.

Paracrine signalling Cell to cell

interaction Signal is produced

for adjacent cells Ex:

neurotransmitters in neurons

Endocrine signalling For hormone For signals that need to

travel over distances Signals are carried by

the blood stream Reaches target cell with

receptors

Adhesion

Adhesion is the property of cells to remain in contact with each other.

Almost all cells of a tissue show this property.Such cells which are in close contact with

each other for a long time form long lasting connections.

Connections are called cell junctions.Nature of connection depends on the tissue

type.

Cell – Cell interactions

Three types based on the functions:Tight junctionsAnchoring junctionsCommunicating junctions

Tight Junctions

Called occluding junctions.

Connect the plasma membranes of adjacent cells.

Prevent leakage of small molecules from between them.

Anchoring junctions

mechanically attach the cytoskeleton of a cell to the cytoskeletons of

other cells to the extracellular

matrix.Usually muscles and

skin epithelium form such junctions.

They can withstand some mechanical stress.

Desmosomes connect the cytoskeletons of adjacent cells.

hemidesmosomes anchor epithelial cells to a basement membrane.

Proteins called cadherins form these links.

Communicating junctions

Cells communicate with adjacent cells through direct connections, called communicating junctions.

Direct physical contact is established.

Allows small molecules to pass.

Gap junctions

Communicating junctions called gap junctions are composed of structures called connexons, complexes of six identical transmembrane proteins.

Allows passage of larger molecules like sugar and amino acids.

They are also regulated by hydrogen and calcium ions.

Cell – matrix interactions

Anchoring junctions called adherens junctions are another type of junction that connects the actin filaments of one cell with those of neighboring cells or with the extracellular matrix.

Its mediated by a protien called integrin.

Classification of cell junctions

Based on localization between cells

Cell – Matrix Adhesions: Hemidesmosomes

A structure that joins a cell to its basal membrane rather than to another cell.

The basal lamina is a layer of extracellular matrix secreted by the epithelial cells.

Cytosolic plectin plate, integrin and lamins help in the formation.

Cell junctions based on functions

Adhesion by Cadherins and Integrins

Cadherin Integrin

Cadherins

Connexin

Gap junction proteinsTransmembrane

proteins

Homophilic Heterophilic

When same kind of receptors bind from 2 cells to form the junction.

When different kind of receptors bind from 2 cells to form the junction.

Classes of adhesion molecules

Mucins Selectins Mucins are a group of serine

and threonine rich proteins and they are heavily glycosylated.

i. Two mucin-like molecules (CD34 and GlyCAM-1) on certain endothelial cells of lymph nodes bind to L- selectin on leukocytes.

ii. PSGL-1 is a mucin-like molecule on neutrophils. It interacts with E-selectin and P-selectin on inflammed vascular endothelium.

Selectin CAMs are responsible for the initial stickiness of leukocytes to vascular endothelial cells.

Glycoproteins that bind to specific carbohydrate groups.

three molecules called L-selectin, E-selectin, and P-selectin.

i. L-selectins are expressed by most leukocytes.

ii. E-selectin and P-selectin molecules are expressed by vascular endothelial cells.

Signalling Molecules

Messengers of cellsFor communicationThey can be compounds like peptides, amino

acids, steroids or even gases.Secreted by signalling cell.Carried out by exocytosis while some by

simple diffusion.

Types

NO gasSteroidsNeurotransmittersPeptide hormones and growth factors

Second messengers

NO: Nitric oxide

Major paracrine signalling molecule.In nervous system, immune system and

circulatory systems.Diffuses easily across plasma membrane.It ultimately alters the activity of intracellular

target enzyme.NO has a very short half life.Its toxic.Therefore, it functions over short distances.Induces relaxation and vaso dilation.

NO

NO is also helps macrophages and neutrophils to kill microorganisms.

CO, carbon monoxide is also used as a signal.It acts same as NO i.e, by stimulating

guanylyl cyclase.It’s a neurotransmitter.

Steroids

Small hydrophobic molecules.Act as hormones.Easily cross the membraneAldosterone – regulates blood pressureCortisol – Acts as a immunosuppressant

Neurotransmitters

Carry signals between neurons i.e., between synapses.

Diverse group of hydrophilic molecules. Hence the are unable to cross the plasma

membrane and bind to receptors.Examples:

Acetylcholine – connects motor nerves to muscles. Histamine – used in CNS Adrenaline – sleep, fight or flight responses, alertness

Action of neurotransmitters

Peptide hormones and growth factors

Widest range of signalling molecules in animals.Size can range from few to a hundred amino

acids.They include peptide hormones, neuropeptides

and growth factors.Peptide hormones:

Insulin: regulates uptake of glucose and stimulates cell proliferation.

Glucagon: Stimulates glucose synthesis. FSH (Follicle Stimulating Hormone): Stimulates growth

of oocytes Prolactin: Stimulates milk production.

Neuropeptides function as neurotransmitters as well as neurohormones. Examples: Enkephalins and endorphins They both have analgesic properties. Decrease pain in CNS. They bind to the same receptors as morphine in the brain

cells.Oxytocin – Smooth muscle contractionVasopressin – stimulates water reabsorbtion

Polypeptide growth factors are signalling molecules that control growth and differentiation of cells.

NGF (Nerve growth factor) – differentiation and survival of neurons.

Epidermal growth factor – proliferation of different types of cells.

Interleukin 2 – Proliferation of T lymphocytes.

Second Messengers

Second messengers are Substances apart from the signalling molecules Used to relay the message Usually used to amplify the signal. Released and broken down by specific enzyme

reactions Localised action

Some examples are: cAMP – cyclic adenosine monophosphate cGMP – cyclic guanosine monophosphate IP3 – inositol triphosphate DAG – diacyl glycerol Ca2+ - Calcium ions

Identify the second messengers

Cell surface receptors

Stuctures on the plasma membraneEach one has unique way of reacting to

different molecules to perform functions.

Forms of receptors

Steroid receptorG protein coupled receptorsTyrosine kinase receptorsCytokine superfamily receptor

Steroid receptors

Found in cytosol, plasma membrane and the nucleas.

Usually have nuclear receptors.Lead to change in gene expression causing

alteration in the transcriptional activity.Some receptors are always bound to the DNA

even when the hormone is not present. Eg: Thyroid hormone receptor.

Some can bind only when the hormone is there. Eg: Estrogen and glucocorticoid receptors.

Many G protien receptors and ion gated receptors also act as steroid receptors.

Structure: Variable domain: the structural component of the

receptor DNA binding region: This region controls the gene to

be activated. Hinge region: Controls movement of receptor Hormone binding domain: the region where the

hormone or ligand binds.

HDAC

Histone deacetylases (HDAC) are enzymes that remove acetyl groups (O=C-CH3) from a histone.

allows the histones to wrap the DNA more tightly.

DNA expression is regulated by acetylation and de-acetylation.

Its action is opposite to that of histone acetyltransferase (HAT).

HAT

Histone acetyltransferases (HAT) are enzymes that acytylate histone protiens by transferring a acetyl group from acetyl CoA.

DNA is wrapped around histones.Therefore, by transferring an acetyl group to

the histones, genes can be turned on and off.In general, histone acetylation increases gene

expression.

Action of steroids

Tyrosine kinase receptors

It’s the largest group of enzyme linked receptors.

Have receptors for most polypeptide growth factors.

Act by phosphorylating the substrate protien.Plays major role in growth and

differentiation.Include receptors for EGF, NGF, PDGF,

insulin, and many other growth factors.

Cytokine Receptors

called the cytokine receptor superfamily.includes the receptors for most cytokines like

interleukin2 and erythropoietin and for some polypeptide hormones (growth hormone)

Associated with non-receptor protein kinases (protein tyrosine kinases) which get activated on ligand binding.

G – Protein coupled receptors

Known as 7TM receptor or seven transmembrane domain receptors.

They pass through the plasma membrane 7 times forming many extracellular loops

They have highly conserved cysteine residues forming disulfide bonds for stability.

They extracellular regions may be glycosylated.The also have trimeric protiens: α, β and γ

protiens which dissociate during the activation of the receptor.

Structure of G – protein linked receptors

Classification

Mechanism

The main response mechanism is by forming cAMP.

But there are 2 pathways: cAMP signalling pathway PIP pathway

cAMP pathway

PIP2 signal pathway

Desensitization

Three general waysInactivation

They can become altered so they can no longer interact with G proteins.

Sequestration They can be temporarily moved to the interior of the

cell (internalized) so that they no longer have access to their ligand

Downregulation They can be destroyed in lysosomes after

internalization.

Rhodopsin like receptors

Rhodopsin is a seven pass transmembrane molecule.

Homologous to G protein coupled receptors.Activating signal is not a molecule, but a

photon of light.This is usually active in olfactory and visual

responses.Also acts as a neurotransmittors.

References

https://en.wikipedia.org/wiki/Cell_surface_receptor

https://www.boundless.com/biology/textbooks/boundless-biology-textbook/cell-communication-9/signaling-molecules-and-cellular-receptors-83/types-of-receptors-381-11607/

https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor

http://www.ncbi.nlm.nih.gov/books/NBK9866/The Cell: A Molecular Approach. 2nd edition

by Cooper and Sunderland

https://moodle.kent.ac.uk/external/mod/book/view.php?id=2396&chapterid=79

http://bpsbioscience.com/cell-surface-receptorshttp://www.scq.ubc.ca/cell-surface-receptors-a-

biological-conduit-for-information-transfer/https://www.glowm.com/section_view/

heading/Cell%2520Membrane%2520Receptors/item/281 : Cell membrane receptors by C V Rao and Carolyn M Klinge

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/moaction/surface.html

http://genome.tugraz.at/MolecularBiology/WS11_Chapter_12.pdf

http://homepage.ntu.edu.tw/~mchuang/Receptor%20signaling.pdf

http://www.columbia.edu/cu/biology/courses/w3041/minden/cell_signaling_notes.pdf

http://www.mhhe.com/biosci/genbio/raven6b/graphics/raven06b/other/raven06b_07.pdf

Cell adhesion and CAMs http://www.cryst.bbk.ac.uk/pps97/assignments/

projects/emilia/Adh_mol.HTM https://www.rndsystems.com/resources/articles/

adhesion-molecules-ii