Hello, in this video we will see the adenylyl cyclase : cAMP 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. Adenylyl cyclase is affected by these two proteins. Gs stimulates adenylyl cyclase and thereby stimulates the pathway. Gi on the other hand inhibits the pathway. Generally speaking, stimulation of the Gs-coupled receptor 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 the pathway involving Gs. Gs protein consists of αs, β, and γ subunits. Under resting state the trimer of these subunits is associated with receptor and α subunit is bound to GDP. The binding of a ligand with the receptor causes conformational changes in receptor and G protein that leads to release of GDP and binding of GTP. This in turn causes dissociation of α subunit and βγ complex. The α subunit travels along the membrane and goes to adenylyl cyclase. Adenylyl cyclase is a membrane-bound enzyme facing the cytosol. αs subunit stimulates this enzyme. The enzyme then converts ATPs into cyclic AMPs. So the concentration of cAMP in the cell increases. Increase cAMP concentration leads to activation of cAMP-dependent PKA. PKA phosphorylates different transporter 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 β1 receptor which is a Gs protein-coupled receptor. Adrenaline stimulates this receptor and activates the adenylyl cyclase pathway. This eventually leads to phosphorylation of proteins that sequester Ca in 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. Their activation by glucagon activates this pathway and causes phosphorylation of key enzymes for glycogenolysis. This ultimately leads to the release of glucose by the liver. Now let's talk about the termination of the signal. When the external signal is no longer present, the intracellular signal is terminated. This occurs at multiple levels. First the α subunit itself. It has got GTPase activity. So it hydrolyzes GTP into GDP and inorganic phosphate. The inactive GDP bound α subunit dissociates from the adenylyl cyclase and re-associates with the βγ complex. This prevents further activity of adenylyl cyclase. Next is cAMP. An enzyme called phosphodiesterase breaks the cAMP into AMP. So the concentration of cAMP 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 these contribute to the termination of the signal and response. So this is what happens when a Gs protein-coupled receptor is stimulated. Now let's talk about Gi protein. It has αi and of course β and γ subunits. These subunits follow similar path as Gs protein. Binding of ligand causes release of GDP, binding of GTP and then dissociation of α subunit. Now instead of stimulating, αi in this case inhibits adenylyl cyclase. So all the things that were happening at a baseline rate stop happening. So the activity of the cell decreases. As example let's got to SA node this time. It contains M2 receptor which is a Gi protein-coupled receptor. Acetylcholine activates this receptor and inhibits adenylyl cyclase activity. This ultimately leads to decreased impulse generation and a fall in heart rate. Next example, pancreatic β cells. They have α2 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 Gs-coupled receptor increases the activity of the cell and stimulation of Gi-coupled receptor decreases the activity. For example, cardiac myocyte contains both β1 receptors which are coupled with Gs protein, and M1 receptors which are associated with Gi protein. Sympathetic nerve terminals release noradrenaline. It stimulates the β1 receptor and increases the cAMP 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 simulates the M2 receptor and decreases the cAMP level. This leads to a decrease in contractility which contributes to a decrease in cardiac output under the 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, adrenaline and acetyl choline both are controlling contractility by following same second messenger pathway. So this was all about the adenylyl cyclase : cAMP pathway. Let's have a quick summary. First Gs. Under resting state, α, β, and γ subunits are associated with receptor and α subunit is bound to GDP. Activation of the receptor causes release of GDP and binding of GTP. This causes release of the αs subunit that activates adenylyl cyclase. Adenylyl cyclase converts ATP into cAMP which activates PKA. Activated PKA phosphorylates various target proteins and modulate 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 α subunit that inactivates itself and thereby adenylyl cyclase, phosphodiesterase that degrades cAMP and phosphatases that dephosphorylate the target proteins. Gi protein inhibits adenylyl cyclase and prevents all these from happening. This generally decreases cellular activity. That's it for this video. If you feel this video will help your friends and colleagues, please share it with them too. And don't forget to subscribe because lots more to come. At nonstop neuron, learning medical concepts is as easy as watching cartoons. Thanks for watching, see you in the next video.