About Glucagon and cAMP


 

 Answer to Hormone Question H-04

 

Answer (e): Glucagon provokes the formation of cAMP inside the cell, via a G Protein-Adenyl Cyclase mechanism.

 

 

cAMP or 3’5’AMP is a nucleotide formed from ATP by the action of Adenyl cyclase, a transmembrane protein whose cytoplasmatic domain catalyze the following reaction:

 

             

 

 cAMP was the first compound to be described as a second messenger of the endocrine system. Observe that one phosphate group is bound by two ester phosphates linkages to the 3’  and the 5’  positions of the sugar, that is why this compound is called 3’5’ AMP. Observe also that these linkages forms a kind of ring or cyclic structure, limited by the Phosphorus  and the Oxygen residues and the 3’ and 5’ carbons. It explains the name of cAMP (Cyclic AMP).

 

The mechanism used by glucagon to increase the concentration of cAMP inside the cell, is the following:

 

Glucagon receptors are located mainly in the hepatic and kidney tissues. Glucagon binds to the receptors, that are coupled to  G Proteins ( Guanin nucleotide binding Proteins) located in the cytoplasmatic side of the plasma membrane.  G proteins are formed by three subunits: alpha, Beta and Gamma.

 

There are four main families of a subunits. The alpha subunit is responsible of the kind of response inside the cell, since it is specific for the effector protein.

 

The a subunit that interact with Adenyl clyclase is called Gas, and the G protein that contains it is referred as Gs Protein.

 

The interaction Glucagon/Receptor provokes the activation of a Gs Protein, since the binding of Glucagon to the receptor triggers the general process for Hormones that use the receptor-G Protein mechanism:

 

1.- the interchange of a GDP, attached to the alpha subunit, by GTP

 

2.- the dissociation of the formed GTP-alpha subunit complex, of the Beta-Gamma subunits dimmer.

 

3.- The activation of an effector protein by the GTP-a subunit complex.

 

Since Glucagon receptor is associated to a Gs Protein, The released GTP-Gas subunit complex binds to Adenyl cyclase, provoking the formation of cAMP.

 

 

 

 

In the cells stimulated by glucagon, the cAMP initiates an enzymatic cascade that begins with the activation of protein Kinase A (PKA) and whose main results are:

 

a)     increased glycogenolysis

 

b)     Decreased glycogenesis

 

c)      Decreased glycolysis

 

d)     Increased gluconeogenesis

 

e)     increased fatty acid movilization

 

f)       Increased ketogenesis

 

 

Hormones: Answer to H-01


  

Original Question

 

 

The answer is  (a)

 

The mechanism of the “second messenger” is used by hormones that can not cross the plasma membrane, like peptides hormones and hormones derived from amino acids (T3 is an exception, since it has a hydrophobic lateral chain). Since these hormones can not cross the plasma membrane, they interact with a receptor located in the membrane, like this transmembrane protein:

  

 

 

                        

 

 

The interaction between the receptor (a membrane protein that frequently has seven intramembrane domains) and the hormone provokes the activation of one of the G-Proteins, a family of amphipatic proteins associated to the inner surface of the plasma membrane.

 

In this graphic, the receptor is represented as a transmembrane protein in blue, and the G-Protein is represented in pink color:

 

 

 

 

   

  

 

The interaction between the hormone and the receptor provokes changes in conformation of the G-Protein associated to the receptor, facilitating the release of GDP and the binding of GTP in the alpha subunit of the G-Protein.  The alpha subunit-GTP complex dissociates from the Beta-Gamma subunits, and it can produce activation of membrane associated enzymes like Adenyl Cyclase, Phospholipase C or other enzymes, depending on the specific Hormone-Receptor-G Protein system.

 

If the GTP-alpha subunit complex released in the Hormone-Receptor-G Protein System activates Adenyl Cyclase, then this enzyme catalyses the transformation of ATP to cAMP; if the system activates Phospholipase C, then it produces the hydrolysis of phosphatidyl inositol diphosphate, releasing Inositol triphosphate (IP3) and diacylglycerol, that act as second messengers.

 

Molecules as different as cAMP, IP3, diacylglicerol,  Ca++ and Nitric Oxide can function as second messengers.

 

More information about this topic can be found in the following links:

 

Kimball, J.K. :Second Messengers

 

King, M.W. : The Medical Biochemistry Page