Intracellular signalling Flashcards
What is Paracrine signalling?
Paracrine signals are released locally and affect neighbouring cells
How does steroid signalling work?
leave the bloodstream and migrate across the plasma membrane into their target cells. Binding of the hormone to its intracellular receptor induces a conformational change in the receptor that promotes or inhibits transcription of target genes. Every hormone regulates a different set of genes
Process of protein phosphorylation
Some molecules are activated by the addition of a phosphate group by a kinase and inactivated when the same group is removed by a phosphatase
Process of GTP Binding Proteins
G proteins are active when they bind GTP and switched off when GTP is exchanged with GDP
Once activated by GTP binding, these proteins possess an intrinsic GTPase activity and they shut themselves down by hydrolysing their bound GTP into GDP
Types of receptors
G-protein coupled receptors
Enzyme-coupled receptors
Steroid hormone receptors
What are G-protein coupled receptors?
When a G-Protein coupled receptor binds its ligand activates a G-protein which turns on an enzyme
single polypeptide chain that spans the plasma membrane seven times
How do G-protein coupled receptors work?
three protein subunits alpha beta e gamma. In the quiescent state the alpha subunit has GDP bound to it. When the extracellular ligand binds to its receptor the altered receptor activates the G protein by causing the alpha subunit to decrease its affinity for GDP which is then exchanged for a molecular of GTP. The activated alpha subunit with its bound GTP detaches from its beta and gamma subunits which also become activated.
What target enzymes are associated with G-protein coupled receptors?
adenylyl-cyclase- cyclic AMP or cAMP
phospholipase C- inositol triphospahate (IP3)and diacylglycerol (DAG)- second messengers
Chain reaction of adenylyl-cyclase
increase in the intracellular level of cAMP at the expenses of ATP. The cAMP is a small molecule and as such can diffuse freely in the cytoplasm and it activates the cAMP-dependent protein kinase A (PKA). PKA is a kinase and therefore phosphorylates a variety of downstream targets such as the enzyme mediating the breakdown of glycogen into glucose in the skeletal muscle during a “fight or flight” response
Chain reaction of phospholipase C
IP3 diffuses through the cytoplasm and triggers the release of calcium from the endoplasmic reticulum by binding and opening the calcium channels on the ER membrane (sudden increase in intracellular conc)
protein kinase C (PKC) that in turn will phosphorylate a number of target proteins
How is calcium concentration differences between extracellular and intracellular environments maintained?
constant action of calcium pumps that will actively pump calcium from the cytosol into the extracellular fluid or in the ER. There is normally a steep electrochemical gradient for calcium on both sides of the plasma membrane and on the ER membrane
What happens when a signal transiently opens the calcium channels?
calcium will immediately flow in the direction of its gradient and in so doing will increase the concentration of Calcium in the cytosol, sensed by calcium responsive protein calmodulin, conformational change that enables it to wrap around target proteins to activate them. Calmodulin that has bound calcium activates Calcium/Calmodulin-dependent protein kinase C
What are enzyme-coupled receptors?
When a ligand binds to an enzyme-coupled receptor the enzymatic activity of the receptor is activated
cytoplasmic tail of the receptor instead, upon ligand binding activates its enzymatic activity and therefore phosphorylates its own residues (auto-phosphorylation)
How do receptor tyrosine kinases (RTK) receive a signal?
phosphorylates tyrosine on the target proteins. The binding of a signalling molecule to the RTKs causes two receptor molecules to come together in the membrane forming a dimer. The dimer formation activates the kinase function with the result that each receptor phosphorylates the other.
Chain reactions of RTK
adaptor” molecules to the activated receptor that in turns induces Ras to release its GDP and to bind GTP
promotes the activation of a phosphorylation cascade in which a series of protein kinase phosphorylate each other in a sequence
activates the MAP kinase kinase kinase that by phosphorylation activates the MAP kinase kinase that in turns activates a MAP kinase that finally phosphorylate a number of downstream signalling molecules leading mainly to changes in gene transcription of target molecules that will make the cell proliferating.
