Cell Signalling Flashcards
(6 cards)
(m) Outline the main stages of cell signalling:
i. ligand-receptor interaction,
ii. signal transduction (phosphorylation cascade and signal amplification)
iii. cellular responses (change in gene expression) (Knowledge of intracellular receptors is not required)
(a) Ligand-receptor interaction
The ligand / signal molecule is complementary in shape to a specific binding site on the receptor and attaches itself there.
The binding of the ligand to the receptor induces a conformational change in membrane-bound receptor or dimerisation of two membrane-bound receptors. This change in shape activates the receptor, triggering downstream signalling pathways
(i) Signal molecules that are large and/or hydrophilic. A large class of ligand molecules cannot pass through the cell surface membrane of the target cell. Examples include insulin molecule and glucagon molecule. The receptor proteins for these signal molecules have to lie in the cell surface membrane of the target cell and relay the message across the membrane
Cell surface receptors
A cell surface receptor is usually a transmembrane protein embedded in the cell surface membrane of the target cell. It allows the cell to receive the signal coming from outside the cell and respond to it.
(b) Signal transduction
The signal transduction pathway often requires a sequence of changes in a series of different relay molecules in a multistep pathway.
Signal transduction occurs via two main ways, protein phosphorylation in a phosphorylation cascade and the release of second messengers. Such pathways also allow for signal amplification.
(i) Phosphorylation cascade
Protein kinases are enzymes that transfer phosphate groups from ATP to proteins, i.e. phosphorylation.
Protein phosphatases are enzymes that remove phosphate groups from proteins, i.e. dephosphorylation
Many of the relay molecules in signal transduction pathways are protein kinases and they often act on other protein kinases in the pathway.
Each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade.
Relay molecules are usually activated when they are phosphorylated and deactivated when they are dephosphorylated.
(ii) Second messengers
Not all relay molecules in the signal transduction pathway are proteins. Second messengers are small, non-protein, water-soluble molecules or ions
As second messengers are small and water-soluble, they can readily diffuse throughout the cell. In addition to their job as relay molecules, second messengers serve to greatly amplify the strength of the signal. (number of activated product greater than those in the preceding step)
iii) Signal amplification
In other words, a small number of extracellular signal molecules can produce a large cellular response.
Enzyme cascades amplify the cell’s response to a signal. At each catalytic step in the cascade, the number of activated products is much greater than those in the preceding step.
(c) Cellular response
The signal transduction pathway leads to a specific cellular response, which is the regulation of one or more cellular activities. The response may occur in the nucleus or cytoplasm of a cell.
some cellular responses may include:
(i) Regulation of activity of protein (e.g. opening or closing of an ion channel in the cell surface membrane changes membrane permeability);
(ii) Regulation of synthesis of protein by turning specific gene expression on or off in the nucleus;
(iii) Regulation of activity of enzyme (e.g. glycogen phosphorylase);
(iv) Rearrangement of the cytoskeleton of the cell;
(v) Death of the cell (e.g. in apoptosis)
(n) Explain the roles and nature of second messengers (including cyclic AMP)
Second messengers are small, non-protein, water-soluble molecules or ions that relay signals
As second messengers are small and water-soluble, they can readily diffuse throughout the cell. In addition to their job as relay molecules, second messengers serve to greatly amplify the strength of the signal
Cyclic adenosine monophosphate (cAMP)
An enzyme embedded in the cell surface membrane, adenylyl cyclase / adenylate cyclase, when activated by the G protein, can convert many ATP to cAMP molecules.
The cytosolic concentration cAMP is elevated twenty-fold in a matter of seconds, amplifying the signal in the cytoplasm.
It does not persist for long in the absence of the hormone, because another enzyme, called phosphodiesterase, converts the cAMP to AMP, resulting in signal termination.
(o) Explain the role of kinases and phosphatases in signal amplification
- Protein kinases are enzymes that transfer phosphate groups from ATP to proteins, i.e. phosphorylation.
- Protein phosphatases are enzymes that remove phosphate groups from proteins, i.e. dephosphorylation
- Each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade. Each protein kinase can phosphorylate and activate more than one kinase as enzymes remain chemically unchanged at the end and can be reused.
- Relay molecules are usually activated when they are phosphorylated and deactivated when they are dephosphorylated.
(p) Outline how insulin regulate concentration of blood glucose through tyrosine kinase receptor. (The outline should be limited to describing how the ligand induces a conformational change in a membrane-bound receptor to trigger downstream signalling pathways that elicit physiological changes in blood glucose concentration. Details of different second messengers and specific kinases activated in the pathway are not required.)
Insulin and RTK Signalling
(i) Ligand-receptor interaction
During ligand-receptor interaction, binding of insulin to extracellular binding sites of receptor tyrosine kinase causes two RTK proteins to form a dimer.
Dimerisation activates the tyrosine kinase function found in the intracellular tails of RTK
Tyrosine kinase adds phosphate group from ATP molecule to the tyrosine residues on the tail of the other RTK protein by autophosphorylation.
(ii) Signal Transduction
During signal transduction, the activated RTK will trigger the assembly of relay proteins on the receptor tails, activating them.
Activated relay proteins will further recruit and activate other downstream relay molecules and protein kinases.
Each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade.
At each phosphorylation step, each activated kinase is able to activate a large number of the next kinase.
At each catalytic step in the cascade, the number of activated product is always greater than those in the preceding step, resulting in signal amplification
(iii) Cellular Response
Activated relay proteins cause vesicles embedded with glucose transporters to move to the cell surface membrane and fuse with it, thus inserting the transporters into the cell surface membrane.
o This will result in the increase in uptake of glucose i
into muscle cells.
Large number of of glycogen synthase is activated, which will catalyse the synthesis of glycogen from glucose (glycogenesis).
o Thus, binding of 1 insulin molecule to receptors
will lead to the synthesis of large amounts of
glycogen.
Decrease activity or synthesis of enzymes involved in glycogenolysis and gluconeogenesis
(iv) Signal termination:
Insulin is released from receptors, the tyrosine residues are dephosphorylated by phosphatases and the dimer dissociates back into individual RTK proteins. Protein phosphatases inactivate protein kinases by dephosphorylation.
(p) Outline how glucagon regulate concentration of blood glucose through the G-protein linked receptor. (The outline should be limited to describing how the ligand induces a conformational change in a membrane-bound receptor to trigger downstream signalling pathways that elicit physiological changes in blood glucose concentration. Details of different second messengers and specific kinases activated in the pathway are not required.)
Glucagon and GPLR Signalling
(i) Ligand-receptor interaction
During ligand-receptor interaction, binding of glucagon to extracellular side of G protein-linked receptor (GPLR) activates the receptor and causing it to change its conformation.
The cytoplasmic side of the receptor then binds to an inactive G protein, causing G protein to exchange its bound GDP for GTP.
The G protein is activated and dissociates from the receptor. Activated G protein binds and activates adenylate cylase, which catalyse the conversion of large number of ATP to cAMP.
(ii) Signal transduction
During signal transduction, cAMP, a second messenger, binds and activates a large number of protein kinase A (PKA).
Each activated protein kinase will initiate a sequential phosphorylation and activation of other kinases, resulting in a phosphorylation cascade.
At each phosphorylation step, each activated kinase is able to activate a large number of the next kinase.
At each catalytic step in the cascade, the number of activated product is always greater than those in the preceding step, resulting in signal amplification.
The final protein to be activated is glycogen phosphorylase.
(iii) Cellular Response
During cellular response, a large number of glycogen phosphorylase is activated, which will catalyse the breakdown of glycogen into glucose (glycogenolysis).
Cellular response also includes increase synthesis or activity of enzymes involved in gluconeogensis.
(iv) Signal Termination
Glucagon is released from receptor.
The GTPase activity intrinsic to a G protein hydrolyses its bound GTP to GDP.
Phosphodiesterase converts cAMP to AMP
Advantages and Significance of a Cell Signalling System
(a) Specificity in the ligand-receptor interaction allows signal molecule to elicit responses in specific target cells.
(b) The ability of a signal molecule to activate many different target cells simultaneously allow for regulation and control of response.
(c) Signal amplification allows for one signal molecule to trigger a large cellular response.
(d) One signal molecule can activate many signal transduction pathways to trigger numerous cellular reactions simultaneously.
(e) The binding of signal molecule to receptor at cell surface membrane can result in activation of gene transcription in the nucleus.
