 Hi welcome to Physiology Open. In this video we will discuss the mechanism of action of insulin in terms of its signal transduction pathways. Insulin acts by binding to its receptors which are present on the cell membrane of its target cell. Remember that all protein hormones act by binding to cell membrane receptors and insulin is also a protein hormone. Now cell membrane receptors are of three types in general. Iron channel linked receptors, G protein linked receptors and enzyme linked receptors. Insulin receptors are enzyme linked receptors. This family of receptors either are linked to another enzyme like in jack stat pathway or they have inherent or inbuilt enzymatic activity like these insulin receptors which have inherent tyrosine kinase activity. The insulin receptors are present as tetramus that is they have four polypeptides or subunits which assemble to form the receptor. Two of these subunits are alpha subunits while the other two are beta subunits. Alpha subunits project outside the membrane that is from the extracellular part of the receptor which has the binding site for insulin. The beta subunits traverse through the membrane and protrude into the cytoplasm. These units are held together by disulfide bonds. So these bonds are there between two alpha subunits and also between the alpha and beta subunits. It's not anything new you might be knowing that disulfide bonds are the ones which stabilize the three-dimensional structure of proteins it's a concept okay. Anyways this intracellular part is the one which has intrinsic tyrosine kinase activity that is an ability to phosphorylate tyrosine residues. Also the beta subunits have some tyrosine residues. When insulin is not bound to the receptors the tyrosine kinase is inactive. When the insulin binds to the receptors the tyrosine kinase activity of beta subunits activates which then transfer a phosphate group from ATP to tyrosine residues on other beta subunit that is the beta subunits cross-phosphorylate each other. This is also known as autophosphorylation. This phosphorylated receptor now becomes capable of binding to other substances which can be phosphorylated but it does not directly activates the signal transducing pathways. Instead it binds to some adapter protein which couples or links the receptor to further signaling pathways. In this case that adapter protein is insulin receptor substrate. Now these insulin receptor substrates also have a lot of tyrosine residues which are phosphorylated by the tyrosine kinase of the receptor. Now once that happens this insulin receptor substrate becomes a high affinity binding site or we can say docking site for other kinases and adapter proteins. Basically with this it brings the enzyme closer to the site of their action that is the cell membrane. After this the chain of reaction starts in which various kinases get activated for the downstream action to take place. Some of these kinases act on the target in the cytoplasm and some can move into the nucleus. So now let's see these kinase pathway in detail. There are two fundamental signal transducing pathways by which insulin acts. One is a phosphotidilinositol three kinase or PI3 kinase pathway and the other is RASMAP kinase pathway. First we will see PI3 kinase pathway. Phosphatidilinositol three kinase as its name suggests. Phosphorylates are lipid phosphatidilinositol 4-5 bifosphate or PIP2. For this initially it binds to this insulin receptor substrate. So this insulin receptor substrate brings this PI3 kinase closer to its substrate PIP2 which is present on the membrane and also activates it by phosphorylation. Then this PI3 kinase phosphorylates PIP2 at one more site making it phosphatidilinositol 3-4-5 triphosphate. Previously it was 4-5 bifosphate so as its name suggests it is 3 kinase. So it makes it 3-4-5 triphosphate. This is same PIP2 which is acted upon by phospholipase C to form IP3 and DAG in a different signaling pathway. Here it is being acted upon by PI3K thus forming phosphatidilinositol triphosphate. Now this triphosphate also acts as a docking site for two other kinases that is phosphoinositide dependent kinase 1 and protein kinase B. So these kinase come and bind to this triphosphate. Now what happens this PDK1 phosphorylates protein kinase B which is also known as AKT thus activating it. It is this protein kinase B which now dissociates and move into the cytoplasm which then causes insertion of glute pore receptors on the membrane activates glycogen synthase for conversion of glucose to glycogen inactivates glycogen phosphorylase for preventing glycogenolysis and hence causes varied effects of insulin on metabolism. Now let's come to another pathway. So another mechanism by which insulin acts is by activation of RAS map kinase pathway. Now you might have heard about G protein coupled receptors which are cell membrane receptors linked to trimeric G proteins that is G proteins with three sublunits G alpha, G beta and G gamma. Now apart from these trimeric G protein cells also have monomeric G proteins which also have the ability to bind GDP and GTP. In inactive state they are bound to GDP while when active they bind to GTP just like our trimeric G proteins. Now insulin signaling pathway also involves activation of these monomeric G proteins that is RAS protein. How? Well the insulin receptor substrate binds with another adapter protein GRB2 which in turn binds and activates a guanyin exchange factor protein SOS. Don't get bogged down by the name of the protein just pay attention to the concept. Basically a guanyin exchange factor is activated and as its name suggests it will replace the RAS GDP with GTP causing its activation. The activation of RAS in turn leads to activation of kinase cascade including RAF MEK and then ultimately leading to the activation of MAP kinase. These RAF and MEK all are kinases only. We also call this MEK as MAP kinase kinase since it phosphorylates MAP kinases so it is a kinase for a kinase. Similarly RAF is a MAP kinase kinase kinase. Anyways after activation MAP kinase translocates into the nucleus and phosphorylates many transcription factors that regulate expression of important cell cycle and differentiation specific proteins. So that's how insulin has effects on cell proliferation growth and differentiation. Basically if you see both these pathways involve three kinases in PI3K pathway it is PI3K then PDK1 and then protein kinase B while in RAS MAP kinase pathway it is REF MEK and MAP kinase. In summary insulin acts by two signal transduction pathways PI3K pathway responsible for its metabolic actions mainly and there are some survival actions also and RAS MAP kinase pathway responsible for its effects on cell proliferation growth and differentiation. Okay thanks for watching the video. If you liked it do not forget to subscribe to the channel Physiology Open. Thank you.