In the cell, adenylyl cyclases and G-proteins interact to catalyze the formation of  adenosine 3'-5'-monophosphate (cAMP) from 5'ATP.

Function of G-proteins

In general, a g-protein serves as an intermediary between hormone receptors and effector enzymes.  As a result, the g-proteins aid in regulating the metabolism of molecules in response to the hormonal signals and changes.  The g-protein complex consists of alpha, beta, and gamma subunits and following disassociation, the separated portions serve functional roles in the activity of the adenylyl cyclases.

G-protein Complex

(Ref. 1)

When an extracellular hormone binds to the cell receptor, the receptor initiates the ejection of GDP from the G-alpha subunit and initiates the binding of GTP to the G-alpha subunit (2).  This results in the disassociation of G-alpha subunit from the G-beta/gamma complex.  At this point, both the activated G-alpha subunit and released G-beta/gamma complex can stimulate adenylyl cyclase activity.  However, the G-beta/gamma complex can also inhibit the cyclase, only no model for the G-beta/gamma complex's function has been established (3).


(Ref. 4)

Next, the g-alpha subunit with the GTP attached stimulates the adenylyl cyclase by binding to the red region depicted below.

(Ref. 5)

Once bound, the g-alpha subunit initiates a conformational change, which allows the adenylyl cyclase to begin its function (6).
 

Function of the Adenylyl Cyclase

In general, a cyclase serves as an enzyme which catalyzes the cyclization of a compound.  Generally, the adenylyl cyclase serves as an effector enzyme, which catalyzes 5'Adenosine Triphosphate (ATP) into cyclic Adenosine Monophosphate (cAMP).  In order for the adenylyl cyclase to cyclize the ATP, the G-alpha must be attached to the G-alpha binding site.

Adenylyl Cyclase Type V Complexed with G-alpha subunit

(Ref. 7)

Once the g-alpha subunit is bound and the adenylyl cyclase undergoes its conformational change, the C1 and C2 catalytic domains of the cyclase become oriented to begin the intake of ATP and cyclization (6).


(Ref. 5)

The process involves the elimination of a pyrophosphate group from the ATP in order to cyclize the AMP, as depicted below.

Once the cAMP is catalyzed, the GTP on the G-alpha converts to GDP and the G-alpha subunit detaches from the cyclase.  Once detached, the G-alpha subunit reassociates with the G-beta/gamma complex (6).


(Ref. 4)

The production of more cAMP is carried out when another extracellular hormone attaches to the receptor protein and begins the process once again.

It is also important to note that there are nine identified isoforms of adenylyl cyclases.  All of the isoforms are activated by G-alpha subunits, however some can be activated by other molecules such as forskolin or calcium ions.  Each of the isoforms are characterized by distinct biochemical properties and tissue distribution throughout the body (8).  For instance, adenylyl cyclase type V is found in the heart tissue and adenylyl cyclase type II is found in the lungs, however adenylyl cyclase type V also functions as a GTPase-activating protein for G-alpha and enhances the ability of activated receptors to stimulate GTP-GDP exchange on the G-protein complex (9).  In addition to having various functional abilities, the isoforms also have various regulation aspects and for more information on the regulation of adenylyl cyclase isoforms click on the Regulation image below.
 

    References:
    1.  Image Library of Biological Macromolecules.

    2.  Weitmann, S., Wursig, N., Navarro, J.M., Kleuss, C. (1999) Biochem. 38, 3409-3413.

    3.  Weitmann, S., Schultz, G., Kleuss, C. (2001) Biochem. 40, 10853-10858.

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

    5.  Yan, S., Huang, Z., Rao, V., Hurley, J., Tang, W. (1997) J Biol Chem.  272, 18849-18854.

    6.  Parent, C., Borleis, J., Devreotes, P.N., (2001) J Biol Chem. 10.1074/jbc.M106430200.

    7.  Tesmer, J. J. G., Sunahara, R. K., Johnson, R. A., Gosselin, G., Gilman, A. G., Sprang, S. R. (1999) Science 285, 756.

    8.  Onda, T., Hashimoto, Y., Nagai, M. (2001) J Biol Chem. 10.1074/jbc.M107233200.

    9.  Scholich, L., Mullenix, J.B., Wittpoth, C., Poppleton, H.M., Pierre, S.C., Lindorfer, M.A., Garrison, J.C., and Patel, T.B.
        (1999) Science. 283, 1328-1331.
 
 

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