Hello, in this video we will see adenylal cyclase CIMP pathway of intracellular signaling. Let's get started. In the video on G protein coupled receptors, we have seen that two important types of G proteins are Gs and Gi.
Adenylal cyclase is affected by these two proteins. Gs stimulates adenylal cyclase and thereby stimulates the pathway. GI on the other hand inhibits the pathway.
Generally speaking, stimulation of GS coupled receptors lead to an increase in the activity of the cell and stimulation of the GI coupled receptor leads to a decrease in the activity. First let's see pathway involving GS. GS protein consists of alpha-s, beta and gamma subunits.
Under resting state, The trimer of these subunits is associated with receptor and alpha subunit is bound to GDP. The binding of a ligand with the receptor causes conformational changes in the receptor and G protein that leads to release of GDP and binding of GTP. This in turn causes dissociation of alpha subunit and beta gamma complex.
The alpha subunit travels along the membrane and goes to adenylal cyclase. Adenylal cyclase is a membrane bound enzyme facing the cytosol. Alpha S subunit stimulates this enzyme.
The enzyme then converts ATPs into cyclic AMPs. So, the concentration of C-AMP in the cell increases. Increased C-AMP concentration leads to activation of C-AMP dependent protein kinase A. PKI phosphorylates different transport proteins, metabolic enzymes, transcription factors, or structural proteins.
The phosphorylation modulates the activity of these proteins, which in turn affects various cellular functions. As example, let's see what happens in myocardial cells. They contain beta-1 receptors, which is a GS protein coupled receptor.
Adrenaline stimulates these receptors and activates adenylal cyclase pathway. This eventually leads to phosphorylation of proteins that sequester calcium into the sarcoplasmic reticulum. This ultimately causes an increase in the contractility of cardiac myocytes. Another example, liver cells.
They contain glucagon receptors, which are also GS protein coupled receptors. Their activation by glucagon activates this pathway and causes phosphorylation of key enzymes for glycogenolysis. This ultimately leads to release of glucose by the liver. Now let's talk about termination of the signal. When the external signal is no longer present, the intracellular signal is terminated.
This occurs at multiple levels. First, the alpha subunit itself. It has got GTPase activity. So it hydrolyzes GTP into GDP and inorganic phosphate.
The inactive GDP bound alpha subunit dissociates from the adenylal cyclase and re-associates with the beta-gamma complex. This prevents the further activity of adenylal cyclase. Next is C-AMP.
An enzyme called phosphodiesterase breaks the C-AMP into AMP. So the concentration of C-AMP decreases. This contributes to prevent activity of PKA.
Finally, target proteins. Various protein phosphatases cause dephosphorylation of whichever protein that was phosphorylated initially. This reverses the activity of that protein.
All of this contribute to the termination of the signal and response. So this is what happens when a G-S protein coupled receptor is stimulated. Now let's talk about G-I protein. It has alpha-I and of course beta and gamma subunits. These subunits follow the similar path as G-S proteins.
Binding of ligand causes release of GDP, binding of GTP and then dissociation of alpha subunit. Now instead of stimulating, alpha-I in this case inhibits adenylacyclase. So all the things that were happening at a baseline rate stops happening.
So the activity of cell decreases. As example, let's go to assay node this time. It contains M2 receptor which is a GI protein coupled receptor.
Acetylcholine activates this receptor and inhibits adrenal cycle activity. This ultimately leads to decreased impulse generation and fall in heart rate. Next example, pancreatic beta cells. They have alpha-2 adrenergic receptors. Its stimulation by adrenaline inhibits this pathway and decreases insulin release.
In a nutshell, the involvement of GI protein leads to a decrease in cellular activity. Presence of GS and GI in the same cell provides an opportunity to control the same function from both the sides. Stimulation of G-S coupled receptor increases the activity of the cell and stimulation of G-I coupled receptors decreases the activity. For example, cardiac myocyte contains both beta-1 receptors which are coupled with G-S protein and M1 receptors which are associated with G-I protein.
Sympathetic nerve terminals release noradrenaline. It stimulates the beta-1 receptor and increases the CA-MP level. This leads to an increase in contractility, which contributes to increased cardiac output under sympathetic stimulation. On the other hand, parasympathetic nerve endings release acetylcholine. It stimulates M2 receptor and decreases CA-MP level.
This leads to a decrease in contractility, which contributes to decrease in cardiac output under parasympathetic influence. The net effect on contractility depends on which system is predominantly active. This is a great example of how a second messenger system integrates signals from different extracellular messengers to control a single cellular function. In this case, adenaline and acetylcholine both are controlling contractility by following same second messenger pathway. So, this was all about adenylal cyclase CAMP pathway.
Let's have a quick summary. First, Gs. Under resting state, alpha, beta and gamma subunits are associated with the receptor and alpha subunit is bound to GDP.
Activation of the receptor causes release of GDP and binding of GTP. This causes release of alpha s subunit that activates adenylal cyclase. Adenylal cyclase.
converts ATP into CAMP, which activates PKA. Activated PKA phosphorylates various target proteins and modulates their activity. Generally, this leads to an increase in cellular activity.
When the external signal is removed, the intracellular signal is terminated by GTPase activity of alpha-sabinid that inactivates itself and thereby adenylacyclates, Phosphodiester is that degrades CAMP and phosphatases that dephosphorylate the target proteins. GI protein inhibits adenylacyclase and prevents all these from happening. This generally decreases cellular activity. That's it for this video.
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