Friday, March 1, 2013

Signal Transduction Pathway -The cGMP Pathway

In this post, we will discuss about cGMP. Just like cAMP, as we have seen in the previous post, there is another second messenger in animal cells called the cyclic GMP or cyclic guanosine monophosphate, simply written as cGMP. However, its role is not clearly understood as against that of cyclic AMP.

Just like how cAMP is formed, cyclic GMP is formed by the action of enzyme guanylyl cyclase on GTP and degraded by a phosphodiesterase. As we have discussed in earlier posts, that guanylyl cyclase is activated by nitric oxide and carbon monoxide and also by peptide ligands. So, when there is stimulation of guanylyl cyclases, there is elevation of cyclic GMP levels. How does cyclic GMP mediates its action? The action of this cyclic GMP is generally mediated when there is activation of various cGMP-dependent protein kinase. However, cyclic GMP is also known to regulate ion channels and phosphodiesterases.

Lets take an example of very well defined activity of cGMP. cGMP serves as a very important second messenger in a vertebrate eye. Isn't it interesting to know how? It converts the visual signals to nerve impulses as light. Hence, we are able to see.
We all know there is retina in the eye which contains the rod cells (studied in school). Now, these rod cells contains a receptor which is a photoreceptor. This photoreceptor is a G-protein coupled receptor (GPCR) called rhodopsin. Lets understand how this rhodopsin is activated.
A small molecule is associated with rhodopsin called 11-cis retinal. This small molecule absorbs light and isomerizes to all-trans retinal. As a result, it induces a conformational change in rhodposin protein. This activated rhodopsin then activates G protein called transducin. Being a G-protein, transducin has three subunits as α, β and γ. Just to recall, the α-subunit in inactive state is bound to GDP. Since, rhodopsin activates G protein transducin, there is a conformational change where α-subunit is now bound to GTP and is in active state. This α-subunit (of transducin) bound to GTP  then stimulates the activity of cGMP phosphodiesterase. Now, being a phosphodiesterase, it reduces the intracellular levels of cGMP. The cGMP has a direct effect on ion channels in plasma membrane and so when there is reduction of cGMP levels in the rod cells of retina, this is translated to nerve impulse as light by the effect of  cGMP on ion channels.

This is how the cGMP functions. In the next post, we will discuss about the phospholipids and Ca2+ signaling.