Cell signalling 1

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Cell signalling Cell signalling By: By: Khuram Aziz Khuram Aziz M.phill biochemiatry M.phill biochemiatry

description

introduction to signalling

Transcript of Cell signalling 1

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Cell signallingCell signalling

•By:By:

Khuram Khuram AzizAziz

M.phill M.phill biochemiatrybiochemiatry

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• Cellular SignalingCellular Signaling• Many living organisms contain Many living organisms contain

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

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Environmental stimuliEnvironmental stimuli

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

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

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• Various environmental stimuli exist that Various environmental stimuli exist that initiate signal transmission processes in initiate signal transmission processes in multicellular organisms; examples include multicellular organisms; examples include photons hitting cells in the  hitting cells in the retina of the eye, of the eye,

 and  and odorantsbinding to binding to odorant receptors in  in the the nasal epithelium..  Certain microbial  Certain microbial molecules, such as viral molecules, such as viral nucleotides and  and protein protein antigens, can elicit an , can elicit an immune system response against invading  response against invading pathogens mediated by signal transduction  mediated by signal transduction processes.processes.

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Types of cellular Types of cellular signalingsignaling

• Extra cellular signaling or chemical Extra cellular signaling or chemical signalingsignaling

• Cell”s direct signaling or Cell”s direct signaling or intracellular signallingintracellular signalling

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Ectracellular signalingEctracellular signaling

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

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

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

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autocrine signalingautocrine signaling,,

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

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Cell direct contact Cell direct contact signallingsignalling

• Three typesThree types• Gap junctionsGap junctions• Surface protein interactionsSurface protein interactions• ReceptorsReceptors

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Receptors Receptors

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

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

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

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StructureStructure

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

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Binding and activationBinding and activation

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

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

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

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Constitutive activityConstitutive activity

• A receptor which is capable of producing its A receptor which is capable of producing its biological response in the absence of a bound biological response in the absence of a bound ligand is said to display "constitutive activity".ligand is said to display "constitutive activity".

 The constitutive activity of receptors may be  The constitutive activity of receptors may be blocked by blocked by inverse agonist binding. Mutations  binding. Mutations in receptors that result in increased in receptors that result in increased constitutive activity underlie some inherited constitutive activity underlie some inherited diseases, such as precocious puberty (due to diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). thyroid-stimulating hormone receptors).

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Ligands Ligands

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

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

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

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

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Cell surface receptorCell surface receptor

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

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

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TypesTypes

• Receptors can be roughly divided Receptors can be roughly divided into two major classes: into two major classes: intracellular receptors and  receptors and extracellular receptors. receptors.

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Extracellular receptorsExtracellular receptors• Extracellular receptors are Extracellular receptors are integral transmembrane proteins

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

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• These are transmembrane recptors These are transmembrane recptors of various typesof various types

• Having 3 domainsHaving 3 domains

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The extracellular domainThe extracellular domain

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

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the transmembrane the transmembrane domainsdomains

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

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

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intracellular (or intracellular (or cytoplasmic) domain) domain

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

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

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

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• processes through membrane processes through membrane receptors involve the External receptors involve the External Reactions, in which the ligand binds Reactions, in which the ligand binds to a membrane receptor, and the to a membrane receptor, and the Internal Reactions, in which Internal Reactions, in which intracellular response is triggered.intracellular response is triggered.

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• Based on structural and functional Based on structural and functional similarities, membrane receptors are similarities, membrane receptors are mainly divided into 3 classes: The mainly divided into 3 classes: The ion channel-linked receptor; The ; The enzyme-linked receptor and  and G protein-coupled receptor..

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Ion channel linked receptors• Ion channel linked receptors are ion- are ion-

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

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Enzyme-linked receptorsEnzyme-linked receptors

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

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G protein-coupled G protein-coupled receptorsreceptors

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

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• Signal transduction through membrane Signal transduction through membrane receptors usually requires four characters:receptors usually requires four characters:

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

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

four Stages of Signal Transductionfour Stages of Signal Transduction

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

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

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Three Stages of Signal Three Stages of Signal TransductionTransduction

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• Detailed role of G-protein in signal Detailed role of G-protein in signal transductiontransduction

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