how do cells communicate
- Cells communicate by detecting and sending a variety of chemical signals.
-Signalling cells release many different signal molecules that serve as chemical messengers (eg proteins, small peptides, amino acids etc) - These signal molecules bind to receptor proteins on the surface or in in the interior of target cells, which then initiates a response in the target cell
communication between cells can occur by
1. direct contact
2. secreted molecules that diffuse locally or travel to other tissues to trigger a response in target cells
what are the three stages of cell signalling
- signal reception
- signal tranduction
- cellular response
what is signal reception? how does signal reception occur and what are the different types of signal receptor proteins
Signal reception: refers to the target cell’s detection of an extracellular signal molecule.
- A signal is detected when a signal molecule binds to a specific receptor protein located at the cell’s surface or inside the target cell, examples include hormones and neurotransmitters.
Ligand-receptor interaction is highly specific:
- The signal molecule acts as a ligand, binding to a specific complementary site on the target cell’s receptor to form a ligand-receptor complex.
- This causes the receptor protein to undergo a conformation change. For many receptors, this change in conformation directly activates the receptor, enabling it to interact with
other molecules in the cell.
There are two kinds of signal receptor proteins:
- cell surface / extracellular / transmembrane receptors (located on the cell surface membrane)
- intracellular receptors (located inside the cell)
ligand: any molecule that binds to specific sites on another molecule, often a larger one
signal transduction
Signal Transduction: process by which a target cell converts an extracellular signal into an intracellular signal that results in a specific cellular response.
- The formation of the activated ligand-receptor complex changes the conformation of the receptor protein, initiating the process of transduction.
- most of the time, with cell surface receptors, transduction occurs via a multistep signal transduction pathway consisting of a series of relay molecules.
- These relay molecules are usually proteins such as enzymes that operate in a specific sequence.
- Each protein in the pathway typically acts by altering the conformation of and hence activating or inhibiting the protein immediately downstream.
- As the conformational changes are usually brought about by phosphorylation, the relay proteins in a signal transduction pathway are sequentially phosphorylated.
- This forms a phosphorylation cascade that transmits the signal received at the cell surface into the cell
- Transduction may also involve non-protein molecules that function as second messengers
- Second messengers through diffusion, rapidly relay the signal from the cell surface into the cell interior.
cellular response
- A signal transduction pathway eventually leads to the regulation of one or more cellular activities.
- The response may occur in the cytoplasm (cytoplasmic response) or may involve action in the nucleus (nuclear response)
- Cytoplasmic response involves mainly changes in cell metabolism, including:
1. regulation of enzyme activity such as activation of cytoplasmic enzymes or other proteins.
2. cytoskeletal arrangement. - Nuclear response involves changes in gene expression such as
1. turning specific genes on or off in the nucleus, and hence synthesis of enzymes or other proteins.
what are cell surface receptors
- Cell surface receptors are present as transmembrane proteins embedded in the cell surface / plasma membrane of target cells
Four main types:
1. G-protein linked receptors
2. Receptor tyrosine kinases
3. Ion channel receptors (or ligand-gated ion channels)
4. Integrin receptors
action of cell surface receptors:
- Hydrophilic or water-soluble molecules are unable to diffuse across the hydrophobic core of the cell surface membrane.
- They thus bind to specific sites on cell surface receptor proteins. -> cell surface receptors transmit extracellular signal information into the cell via conformational changes or subunit aggregation, becoming activated.
- The activated receptors then initiate one or more intracellular signal transduction pathways.
for cell surface receptor signalling:
- a multistep signal transduction pathway involving a series of relay molecules occurs, resulting in a cascade of intracellular molecular interactions that relays the extracellular signal from the receptor at the cell surface to target molecules in the cell, leading to a particular cellular response.
- As the original signal molecule is not physically passed along the transduction pathway, the signal received by a cell is relayed along the transduction pathway via conformational changes of relay proteins, brought about by phosphorylation which activates protein
protein phosphorylation and dephosphorylation
phosphorylation: process where a protein kinase, an enzyme (PK), transfers phosphate groups from ATP to a protein
dephosphorylation: process where protein phosphatases (PP), an enzyme which rapidly removes phosphate groups from proteins
The action of the PK and PP enables the following:
- PK phosphorylates and thus activates other protein kinases -> turns on the signal transduction pathway
- PP dephosphorylates and inactivates other protein kinases. -> turns off the signal transduction pathway when the initial signal (signal molecule) is no longer present.
- This allows protein kinases to be available for reuse
- after dephosphorylation, the cell is able to respond again to another extracellular signal. (The reverse may also be true with regards to the effects of the enzymes PK and PP)
- activity of protein regulated by phosphorylation depends on balance in the cell between active kinase molecules and active phosphatase molecules
- phosphorylation and dephosphorylatioin system acts as a molecular switch in cell, turning cellular activities on or off as required
what is a phosphorylation cascade
it is a series of different molecules in a pathway that are phosphorylated in turn, each molecule adding a phosphate group to the next on in line
how does phosphorylation cascade cause protein to change:
- during a phosphorylation cascade, the signal is transmitted by a cascade of sequential protein phosphorylation-> results in interaction between newly added phosphate group with charged / polar amino acids -> conformational change of protein
- hence protein changes form inactive to active form (NOTE: not always true as phosphorylation can sometimes decrease protein activity)
what are second messagers? what do they do
second messagers: Non-protein signal molecules (includes small, non-protein, water-soluble molecules or ions)
function:
- Second messengers serve to transmit the message carried by the extracellular signal molecule - the first messenger - into the target cell’s interior.
how?
- Binding of first messenger onto receptors stimulate an increase in the concentration of second messengers.
- The small and water-soluble second messengers can readily spread throughout the cytosol by diffusion.
- As there is a large variety of relay proteins that are sensitive to the cytosolic concentration of second messengers, binding of second messengers to these proteins can alter the behaviour of the relay proteins
- As they often stimulate a variety of cellular activities, second messengers enable cells to mount a large-scale, coordinated response following stimulation by a single extracellular signal molecule.
common second messengers
- cyclic AMP
- calcium ions, Ca2+
- inositol trisphosphate (IP3)
- diacylglycerol
what are g-protein linked receptors (GLPR)? structure of GPLR?
GPLRs: cell surface receptors that work with the help of G proteins (Guanosine triphosphate [GTP] binding protein), which are located on the cytoplasmic side of the cell surface membrane.
- GPLRs are the most common type of cell surface receptors, used by many different signal molecules such as hormones and neurotransmitters and possess diverse functions (e.g. glucagon receptors)
Primary Structure: Each G-protein linked receptor is made up of 1 polypeptide chain.
Secondary Structure: The single polypeptide chain comprises seven α-helices spanning the cell surface membrane, connected by non-helical segments.
Tertiary Structure:
- Hydrophobic interactions between the seven transmembrane α-helices result in a barrel-shape conformation for the receptor
- Hydrogen bonds and a highly conserved disulfide linkage between the non-helical segments (also known as inter-helical loops) also stabilise the protein.
- The N-terminus and 3 non-helical segments form the extracellular domain of GPLR.
- The seven α-helices form the membrane-embedded domain
- C-terminus and 3 non-helical segments form the intracellular domain of GPLR.
- A GPLR has different binding sites for the
specific signal molecule (facing the exterior) and G protein (facing the cell interior)
structure and function of GPLR
structure: Hydrophilic amino acid residues form the inter-helical loops and N and C termini
function: Enables the extracellular and intracellular domains to be soluble in aqueous medium and also interact with water-soluble ligands and G-protein
structure: Hydrophobic amino acid residues are primarily found in the seven transmembrane α-helices. Hydrophobic interactions exist between the α-helices and also with the hydrophobic fatty acid tails of phospholipids in the membrane bilayer
function: Enables the membrane-embedded domain to be stabilised and embedded within the
membrane bilayer
structure: Extracellular domain contains specific amino acids at signal-binding site
function: Enables signal-binding site to have specific 3D conformation that allows for interaction with specific ligand. Results in a huge diversity of ligands that different GPLRs can bind to.
structure: Intracellular domain contains specific amino acids at G-protein interaction site
function: Enables G-protein interaction site to have specific 3D conformation to bind and activate G-protein
structure: Binding of ligand to GPLR causes a conformational change in protein, allowing it to interact with G-protein
function: Enables GPLR to initiate signal transduction pathways via activation of G-protein
what are the working principles of GPLR
- The G protein (on cytoplasmic side of membrane) mediates the passage of the signal from the membrane surface into the cell interior, by functioning as a molecular switch that is either on or off, depending on whether GDP or GTP is attached.
- When GDP is bound to the G protein, the G protein is inactive.
- GTP bound to G protein, G protein is active
- The GPLR and G protein work together with another protein referred to as the target protein (or effector), which is usually an enzyme
how is signalling mediated by GPLR after a signal molecule binds to it?
- Signal RECEPTION
- The signal molecule (ligand) binds to the (extracellular side of the) GPLR and causes a change in receptor conformation, activating the GPLR. - Signal TRANSDUCTION
- With an increased affinity for the G protein, the cytoplasmic side of the GPLR binds an inactive G protein
- this causes GTP to displace the GDP bound to the G protein -> G protein is activated
- The activated G protein dissociates from the GPLR and diffuses along the membrane.
- The activated G protein binds to a target protein (effector), usually an enzyme (or sometimes a channel protein), thereby altering target protein activity
- Change in target protein (enzyme) activity initiates a cascade of signal transduction events by triggering the next step in the transduction pathway inside the cell, including the:
i) production of cyclic AMP (cAMP) OR
ii) production of inositol trisphosphate (IP3) and release of calcium (Ca2+)
- cAMP, IP3 and Ca2+ serve as second messengers in signal transduction.
3. cellular response
- The last activated molecule in the transduction
pathway triggers a cellular (cytoplasmic or
nuclear) response.
- The intrinsic GTPase activity of the G protein soon hydrolyses its bound GTP to GDP, so that the G protein is inactive again.
- The signal molecule has also dissociated
from the GPLR.
- The inactive G protein leaves the enzyme, which returns to its original inactive state. The G protein is now available for reuse.
cyclic adenosine monophosphate (cAMP)
when extracellular signal molecule that binds to a GPLR -> an enzyme embedded in the plasma membrane, adenylyl cyclase, converts ATP to cyclic AMP (cAMP
metabolism of cAMP
1. An extracellular signal molecule such as epinephrine binds to and activates a GPLR, which activates a specific G protein.
2 The active G protein activates adenylyI cyclase (enzyme), which catalyses the synthesis of many molecules of cAMP. In this way, the normal cellular concentration of cAMP can be boosted 20-fold in a matter of seconds.
- The immediate effect of cAMP is usually the
activation of a serine / threonine kinase called protein kinase A.
The activated kinase then phosphorylates
various other proteins, depending on the cell
type.
- in the absence of the hormone, the number of cAMP molecules does not persist for long as another enzyme, called phosphodiesterase, converts the cAMP to AMP
- Another surge of epinephrine is needed to boost the cytosolic concentration of cAMP again.
Calcium ions (Ca2+) and Inositol Trisphosphate (IP3) function
- many signal molecules in animals induce responses in their target cells via signal transduction pathways that increase the cytosolic concentration of calcium ions (Ca2+)
- Brief increase to the cytosolic concentration of Ca2+ -> activates proteins sensitive to Ca2+ (eg calmodulin) -> induce many cellular responses, (muscle cell contraction, secretion of certain substances, and cell division)
- Although cells always contain some Ca2+, this ion can function as a second messenger because its concentration in the cytosol is normally much lower than the concentration outside the cell.
Low cytosolic Ca2+ is maintained by:
1. Calcium ATPase in the ER membrane sequester Ca2+ from the cytosol into the ER lumen
2. Calcium ATPase in the plasma membrane actively pump Ca2+ from the cytosol into the extracellular fluid
3. Sodium calcium exchangers in plasma membrane couples export of Ca2+ with the facilitated diffusion of Na+ into the cytosol
4. Mitochondrial Ca2+ pumps moves Ca2+ into mitochondria
how does IP3 stimulates the release of calcium from the ER.
in response to a signal relayed by a signal transduction pathway, the cytosolic Ca2+ level may rise, usually by a mechanism that releases Ca2+ from the cell′s endoplasmic reticulum.
- The pathways leading to Ca2+ release involve other second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). These two messengers are produced by the
cleavage of a phospholipid known as PIP2 in the plasma membrane.
how does IP3 stimulate release of calcium from ER:
1. A signal molecule binds to the receptor, leading to the activation of G protein and consequently the enzyme phospholipase C (PLC).
- Phospholipase C (PLC) cleaves a plasma membrane phospholipid called PIP2 into DAG and IP3.
- DAG functions as a second messenger in other pathways.
- IP3 quickly diffuses through the cytosol and binds to an IP3 gated calcium channel in the ER membrane, causing it to open.
- Calcium ions diffuses out of the ER (down concentration gradient),
raising the cytosolic Ca2+ level. - Calcium ions activate the next protein such as calmodulin in one or more signalling pathways, producing a cellular response.
Because IP3 acts before Ca2+, Ca2+ could strictly be considered a third (rather than a second) messenger. However, scientists use the term “second messenger” to refer to all small, non-protein components of signal transduction pathways.
RTK (receptor tyrosine kinases)
RTKs are a major class of cell surface receptors that possesses enzymatic activity.
- The part of the receptor protein extending into the cytoplasm functions as an enzyme known as tyrosine kinase, which catalyses the transfer of a phosphate group from ATP to the amino acid tyrosine on a substrate protein.
Recall:
A kinase is an enzyme that catalyses the transfer of phosphate group from ATP (or GTP) to the targeted protein, leading to its activation or inactivation. - Characteristic of RTKs is their ability to trigger more than one (ten or more) different signal transduction pathways from a single ligand-binding event.
- RTKs can thus activate several different cellular responses and hence display significant functional diversity.
- An example of an RTK is the insulin receptor
Receptor Tyrosine Kinases structure:
before signal molecule binds, the receptor exists as the two individual polipeptide subunits
Each RTK polypeptide (receptor subunit) comprises:
- an extracellular signal-binding site
- an α-helix spanning the membrane
- an intracellular tail containing multiple tyrosines and a tyrosine kinase domain
how does an RTK work in response to signal molecule binding:
- Signal RECEPTION
- The signal molecule (ligand) binds to a subunit of the RTK, resulting in receptor aggregation (two subunits cluster with each other) and dimerisation (two subunits form a dimer)
- Dimerisation leads to the activation of the tyrosine kinase activity of the receptor, resulting in autophosphorylation / cross phoshorylation.
- Each tyrosine kinase domain adds a phosphate from an ATP molecule to a tyrosine on the tail of it’s own or the other polypeptide subunit.
- RTK is activated - Signal TRANSDUCTION
- The activated RTK binds cytoplasmic relay proteins, thereby altering their activity, localisation or ability to interact with other intracellular signalling proteins.
- Each relay protein recognises and binds to a specific phosphorylated tyrosine.
- The bound relay protein becomes activated, in many cases by undergoing a conformational change.
- Each activated relay protein triggers a transduction pathway, thus initiating a cascade of signal transduction events inside the cell. - Cellular RESPONSE
- The last activated molecule in each transduction pathway triggers a cellular (cytoplasmic or nuclear) response.
- since each phosphorylated tyrosine is recognised by a different relay protein -> multiple transduction pathways can be triggered by the activation of one RTK ->
several different cellular responses are generated.
what are the advantages of cell signalling
- signal amplification
- provide more opportunities for coordination and regulation
- contribute to specificity of response
signal amplification
Signal amplification: the process of enhancing signal strength as the signal is relayed through a transduction pathway, resulting in the response being amplified.
Three key features of signal amplification :
- At each catalytic step in the cascade, the number of activated products is much greater than in the preceding step.
- A small number of extracellular signal molecules (first messenger) is sufficient to elicit a cellular response.
- response of the target cell is large, as a large number of activated molecules is produced at the end of the signalling cascade
The amplification effect is possible for two reasons:
- presence of multiple steps in the transduction pathway i.e. between signal reception and the cellular response
- persistence of proteins in the pathway in the active form long enough to process numerous molecules of substrate before they become inactive again
how is blood glucose concentration regulated
- regulated by negative feedback system
- blood glucose concentration rises above set point -> series of reactions are triggered to lower it back to set point -> set point resstored -> negative feedback mechanism will switch off corrective mechanisms such that tere is no further decrease in blood glucose concentration below set point
- antagonistic hormones (oppose each other’s acttion) in regulation of blood glucose concentration: insulin and glucagon
insulin
- Promotes cellular uptake of blood glucose into skeletal muscles and the liver after a meal.
- Stimulates mechanisms to decrease (high) blood glucose concentration to the set point.
Glucagon
- Promotes secretion of glucose into the blood, by hydrolysis of liver glycogen between meals.
- Stimulates mechanisms to increase (low) blood glucose level to the set point.
mechanism of insulin - RTK signalling
- A specific example of RTK signalling is demonstrated by the insulin receptor, triggered by the hormone insulin, leading to the cytoplasmic responses of glucose uptake and storage.
- No second messengers are involved in signal transduction in insulin receptor signalling.
steps:
1. binding of insulin to RTK activates receptor tyroisine kinase activity -> results in auto-phosphorylation and receptor activation
2. relay protein specific to RTK binds to specific phosphorylate tyrosine on receptor -> becomes activated
3. activated relay protein triggers signal transduction pathway
4. activated down-stream relay protein stimulates
- movement of cytoplasmic vesicles carrying glut-4 glucose transporters
- fusion of vesicles with plasma membrane
- more glucose transporters to mediate glucose uptake
4. downstream activated protein leads to activation of glycogen synthase (glycogenesis)
5. active glycogen synthase converts glucose to glycogen
mechanism of glucagon -GPLR signalling
- Binding of hormone glucagon (first messenger) to a specific GPLR activates a specific G protein..
- Activated G protein activates enzyme adenylyl cyclase. Active form of adenylyl cyclase catalyses the synthesis of large amounts of intracellular cAMP (second messenger) from ATP.
- cAMP binds to and activates protein kinase A.
- Active protein kinase A phosphorylates glycogen phosphorylase kinase, activating it.
* PATHWAY 2: Glycogen phosphorylase kinase can also be activated by Ca2+ released from the Ca2+/IP3 pathway - Active protein kinase A also phosphorylates glycogen synthase, inhibiting its catalytic activity, thus preventing the conversion of glucose to glycogen (glycogenesis).
- Activated glycogen phosphorylase kinase
phosphorylates glycogen phosphorylase, the enzyme for hydrolysis of glycogen into glucose, converting it to its active form. - Active glycogen phosphorylase stimulates glycogen hydrolysis to release glucose-1-phosphate (glycogenolysis).
- Glucose eventually formed diffuses into the
bloodstream; more glucose is thus made available to respiring body tissues.
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Carbohydrates28
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Proteins48
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Enzymes30
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Lipids25
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Cell Structure27
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DNA Structure and replication38
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Eukaryotic gene expression49
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Organisation of Eukaryotic genome31
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control of eukaryotic gene expression17
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Gene and Chromosomal Mutations28
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cancer32
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Genetics of Virus26
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Cell signalling24
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Cell membrane33
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Cell and nuclear division46
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stem cells19
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energetics 1: photosynthesis39
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energetics 2: cellular respiration19
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Inheritance40
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Bacteria23
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inheritance II10
