Cell signaling

CELL SIGNALING

By: ASHISH KELWA

Cellular SignalingMany living organisms contain billions of cells that carry out diverse functions. In order for the cells to cooperate, cells need to be able to communicate with each other. Many of the genes that cells are capable of synthesizing are thought to be involved in cellular signaling.

Signal transduction comes from the verb to 'transduce' meaning to 'lead across'. In biology signal transduction is the process by which an extracellular signaling molecule activates a membrane receptor that in turn alters intracellular molecules to create a response. The chemical signal binds to the outer portion of the receptor, changing its shape and conveying another signal inside the cell.

Environmental stimuliWith single-celled organisms, the variety of signal transduction processes influence its reaction to its environment.

With multicellular organisms, numerous processes are required for coordinating individual cells to support the organism as a whole; the complexity of these processes tend to increase with the complexity of the organism.Sensing of environments at the cellular level relies on signal transduction; many disease processes, such as diabetes and heart disease arise from defects in these pathways, highlighting the importance of this process in biology and medicine.

Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye, and odorants binding to odorant receptors in the nasal epithelium. Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune system response against invading pathogens mediated by signal transduction processes.

Types of cellular signalingExtra cellular signaling or chemical signaling.

Cell's direct signaling or intracellular signaling.

Extracellular signalingSignaling by extracellular, secreted molecules can be classified into three types — endocrine, paracrine, or autocrine — based on the distance over which the signal acts.

Endocrine signalingIn endocrine signaling, signaling molecules, called hormones, act on target cells distant from their site of synthesis by cells of endocrine organs. In animals, an endocrine hormone usually is carried by the blood from its site of release to its target.

Paracrine signalingIn paracrine signaling, the signaling molecules released by a cell only affect target cells in close proximity to it. The conduction of an electric impulse from one nerve cell to another or from a nerve cell to a muscle cell (inducing or inhibiting muscle contraction) occurs via paracrine signaling.

Autocrine signalingCells respond to substances that they themselves release. Many growth factors act in this fashion, and cultured cells often secrete growth factors that stimulate their own growth and proliferation. This type of signaling is particularly common in tumor cells, many of which overproduce and release growth factors that stimulate inappropriate, unregulated proliferation of themselves as well as adjacent non tumor cells; this process may lead to formation of tumor mass.

Cell direct contact signalingThree types:

Gap junctions

Surface protein interactions

Receptors

Receptors A receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighboring cells or the wider environment within an organism. These signals tell a cell to do something—for example to divide or die, or to allow certain molecules to enter or exit the cell.

Receptors are protein molecules, embedded in either the plasma membrane (cell surface receptors) or the cytoplasm (nuclear receptors) of a cell, to which one or more specific kinds of signaling molecules may attach.

Types of ReceptorsThere are a number of receptor classes that are used in different signaling pathways.

The two more predominant are:

The conformational change in the receptor upon ligand binding activates a G protein, which in turns activates an effector protein that generates a second messenger.

These receptors have a catalytic activity that is activated by binding of the ligand. An example are tyrosine-kinase receptors. Binding of an often dimeric ligand induces dimerization of the receptors that leads to cross phosphorylation of the cytosolicdomains and phosphorylation of other proteins.

A molecule which binds (attaches) to a receptor is called a ligand, and may be a peptide (short protein) or other small molecule, such as a neurotransmitter, a hormone, a pharmaceutical drug, or a toxin. Each kind of receptor can bind only certain ligand shapes. Each cell typically has many receptors, of many different kinds. Simply put, a receptor functions as a keyhole that opens a biochemical pathway when the proper ligand is inserted.

StructureThe shapes and actions of receptors are studied by X-ray crystallography, dual polarization interferometry, computer modelling, and structure-function studies, which have advanced the understanding of drug action at the binding sites of receptors. Structure activity relationships correlate induced conformational changes with bio molecular activity, and are studied using dynamic techniques such as circular dichroic and dual polarization interferometry.

Binding and activationLigand binding is an equilibrium process. Ligands bind to receptors and dissociate from them according to the law of mass action.

One measure of how well a molecule fits a receptor is the binding affinity, which is inversely related to the dissociation constant Kd. A good fit corresponds with high affinity and low Kd. The final biological response (e.g. second messenger cascade, muscle contraction), is only achieved after a significant number of receptors are activated.

The receptor-ligand affinity is greater than enzyme-substrate affinity. Whilst both interactions are specific and reversible, there is no chemical modification of the ligand as seen with the substrate upon binding to its enzyme.

Constitutive activityA receptor which is capable of producing its biological response in the absence of a bound ligand is said to display "constitutive activity". The constitutive activity of receptors may be blocked by inverse agonist binding. Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors).

Ligands (Full) agonists are able to activate the receptor and result in a maximal biological response. Most natural ligands are full agonists.

Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists.

Antagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists.

Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity.

Cell surface receptorCell surface receptors (membrane receptors, transmembrane receptors) are specialized integral membrane proteins that take part in communication between the cell and the outside world. Extracellular signaling molecules (usually hormones, neurotransmitters, cytokines, growth factors or cell recognition molecules) attach to the receptor, triggering changes in the function of the cell. This process is called signal transduction.

The binding initiates a chemical change on the intracellular side of the membrane. In this way the receptors play a unique and important role in cellular communications and signal transduction.

TypesReceptors can be roughly divided into two major classes:

Intracellular receptors

Extracellular receptors.

Extracellular receptorsExtracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the conformation of the inside part of the receptor. These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.

These are trans membrane receptors of various types

Having 3 domains

o Extracellular Domain

oTransmembrane domain

o Intracellular domain

The extracellular domainThe extracellular domain is the part of the receptor that sticks out of the membrane on the outside of the cell or organelle. If the polypeptide chain of the receptor crosses the bilayer several times, the external domain can comprise several "loops" sticking out of the membrane.

The Transmembrane DomainsIn the majority of receptors for which structural evidence exists, transmembrane alpha helices make up most of the transmembrane domain. In certain receptors, such as the nicotinic acetylcholine receptor, the transmembrane domain forms a protein-lined pore through the membrane, or ion channel. Upon activation of an extracellular domain by binding of the appropriate ligand, the pore becomes accessible to ions, which then pass through.

In other receptors, the transmembrane domains are presumed to undergo a conformational change upon binding, which exerts an effect intracellularly. In some receptors, such as members of the 7TM superfamily, the transmembrane domain may contain the ligand binding pocket.

Intracellular (or cytoplasmic) domainThe intracellular (or cytoplasmic) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamentally different ways for this interaction:

The intracellular domain communicates via specific protein-protein-interactions with effector proteins, which in turn send the signal along a signal chain to its destination.

With enzyme-linked receptors, the intracellular domain has enzymatic activity. Often, this is a tyrosine kinase activity. The enzymatic activity can also be located on an enzyme associated with the intracellular domain.

Based on structural and functional similarities, membrane receptors are mainly divided into 3 classes:

Ion channel-linked receptor;

Enzyme-linked receptor and

G protein-coupled receptor.

Ion channel linked receptorsIon channel linked receptors are ion-channels (including cation-channels and anion-channels) themselves and constitute a large family of multipass transmembrane proteins. They are involved in rapid signaling events most generally found in electrically excitable cells such as neurons and are also called ligand-gated ion channels. Opening and closing of Ion channels are controlled by neurotransmitters.

Enzyme-linked receptorsEnzyme-linked receptors are either enzymes themselves, or are directly associated with the enzymes that they activate. These are usually single-pass transmembrane receptors, with the enzymatic portion of the receptor being intracellular. The majority of enzyme-lined receptors are protein kinases, or associate with protein kinases.

G protein-coupled receptorsG protein-coupled receptors are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. These receptors activate a G protein ligand binding. G-protein is a trimeric protein. The 3 subunits are called α、β and γ. The α subunit can bind with guanosine diphosphate, GDP. This causes phosphorylation of the GDP to guanosine triphosphate, GTP, and activates the α subunit, which then dissociates from the β and γ subunits. The activated α subunit can further affect intracellular signaling proteins or target functional proteins directly.

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Signal transduction through membrane receptors usually requires four characters:

Extracellular signal molecule: an extracellular signal molecule is produced by one cell and is capable of traveling to neighboring cells, or to cells that may be far away.

Receptor protein: the cells in an organism must have cell surface receptor proteins that bind to the signal molecule and communicate its presence inward into the cell.

Four Stages of Signal Transduction

Intracellular signaling proteins: these distribute the signal to the appropriate parts of the cell. The binding of the signal molecule to the receptor protein will activate intracellular signaling proteins that initiate a signaling cascade (a series of intracellular signaling molecules that act sequentially).

Target proteins: the conformations or other properties of the target proteins are altered when a signaling pathway is active and changes the behavior of the cell.

Three Stages of Signal Transduction

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