1. Hormone (in red) interacts with receptor (R)

2. Receptor (R) binds to G complex ( Gb(beta & gamma)-Ga(alpha))

3. Receptor-G complex interaction causes Ga subunit to
    bind GTP in place of GDP.

4. Binding of GTP causes Ga subunit to activate adenyl
    cyclase.

5. Activated adenyl cyclase converts ATP to cAMP as long
    as the Ga subunit is activated.

6. Hormone binding is transient and loss of binding to
    receptor results in conversion of GTP bound to subunit
    Ga to GDP leading to inactive state (REF.1).
 
 

The images below show the regulation of an adenylate cyclase in a step by step manner:

Step #1: Resting state- receptor binding site is unoccupied. G-Protein associated with internal surface of membrane, but not with receptor, is associated in trimer with GDP bound to Galpha subunit. Adenylate cyclase is inactive.

Step #2: Bound ligand. Ligand binds to receptor and conformational change transmitted to cytosolic domain of receptor which permits binding of Galpha.

Step #3: GTP/GDP exchange and adenylate cyclase activation.  Conformational change in Galpha following receptor association leads to exchange of GDP for GTP and dissociation of Galpha from Gbeta and gamma. Galpha migrates in plane of membrane, associates with adenylate cyclase and activates it. cAMP produced from ATP.

Step#4: GTP hydrolysis- slow hydrolysis of GTP to GDP leads to dissociation of Galpha from adenylate cyclase and reassociation with Gbeta and gamma. Adenylate cyclase inactive (REF.2).
 

        cAMP

        -Functions as a cell-specific and hormone specific "second messenger" in response to several
          different non-steroid hormones.

        -Within the cell, cAMP activates protein kinases, which utilize ATP to phosphorylate specific
          substrate proteins.

        -As a result, in the phosphorylated form, these proteins substrates become active and carry out the
         specific function corresponding to hormone stimulation.

                                  Adipose                        epinephrine;                  increase in triglyceride hydrolysis
                                                                ACTH;                        decrease in amino acid uptake
                                                                glucagon

                            Liver                            epinephrine;                  increase in conversion of glycogen
                                                                norepinephine;               to glucose
                                                                glucagon                       inhibition of synthesis of
                                                                                                     glycogen
                                                                                                     increase in amino acid uptake
                                                                                                     increase in gluconeogenesis

                            Follicle                          FSH; LH                      increase in synthesis of estrogen,

                            Adrenal cortex                ACTH                         increase in synthesis of
                                                                                                     aldosterone, cortisol

                            Cardiac muscle              epinephrine                   increase in contraction rate

                            Thyroid                         TSH                            secretion of thyroxin

                            Bone cells                      Parathyroid                  increase in resorption of calcium
                                                                 hormone                       from bone

                            Skeletal muscle               epinephrine                  conversion of glycogen to glucose

                            Intestine                         epinephrine                    fluid secretion

                            Kidney                           vasopressin                   resorption of water

                            Blood platelets                prostaglandin I               inhibition of aggregation and
                                                                                                      secretion

        DISEASES

Once a G-protein is activated it can stay that way for a few seconds, or in some cases a few minutes, because it has a kind of internal timer. The cellular activity caused by the G-protein operates according to that same timer.

For example, if the G-protein's internal timer is set for 10 seconds, it will enlist an effector protein (adenyl cyclase) to help the cell produce as much cAMP as it can in 10 seconds.

Disease occurs when any alteration in the pattern of signal reception or the process of transforming the G-protein from is "off" to "on" state (or the reverse)(REF.4).

      Examples:

(REF.7)

          Bacterium Vibrio cholerae

                -Secretes a toxin which alters the G-protein, leaving it in the "on" position.

                  -Which is achieved by the cholera toxin inhibiting the conversion of GTP bound to Galpha to
                  GDP thus maintaining the activation of adenyl cyclase.

                  -Which in turn makes the intracellular cAMP persistently high.

                - As a result the excessive secretion of Na+ and water.

                -Which prevents the normal absorption of salt and water by the intestines.  Furthermore, the
                  loss of salt and water can lead to dehydration or even death.
 

         Bacterium pertussis

               - Secretes a toxin of two components

               -One component makes the Galpha unable to bind adenylate cyclase

               -The second component is an adenylate cyclase

               - Combined effect is increases cAMP

               -As a result airway cells secrete mucous, whooping cough (REF.5).
 

          Tumors

               -It has been shown that mutated and overactive G-proteins are a characteristic of some tumors.
 

         Alcholism and Diabetes

               -Researches believe that there may be some symptoms from both (alcholism and diabetes) that
                are due to altered signalling via G-proteins (REF.4).
 

         McCune-Albrights syndrome

                -An overactive G-protein is found in this rare genetic endocrine disorder that is characterized
                 by so called "cafe au lait" spots on the skin (REF.6).
 
 

References:

    1.  http://www.people.virginia.edu/~rjh9u/campanim.html

    2.  http://www.nottingham.ac.uk/biochemcourses/students/es/gprof.html#gprot1

    3.  Purves, Dale.  Neuroscience. Sinaner: Massachusetts.  1997:  pp 139.

    4.  http://www3.utsouthwestern.edu/library/speccol/archives/nobel/cell_talk.htm

    5.  http://www.nottingham.ac.uk/biochemcourses/students/es/es1.html#fusion

    6.  http://www.nobel.se/medicine/laureaates/1994/press.html

    7.  http://www.profiles.nlm.nih.gov/GG/Views/Exhibit/narrative/discovery.html

    8.  http://www.pnb.sunysb.edu/faculty/johnson/Schemes.htm

    9.  http://www.people.virginia.edu/~rjh9u/secmess.html