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Cyclic AMP and Hormone Action

From the Meek to the Mighty


Hormones are important regulators of biological processes. Those
that work through the action of 3-5-cyclic AMP (cAMP) control enzymes by
using ATP to phosphorylate serine and threonine groups on target enzymes.
These so-called protein kinases represent a sequel of catalytic steps
designed to amplify the action of the hormone. The key word here is
catalytic, which means many progeny can come from one. There is a
pattern to many protein kinase-dependent processes and this tutorial will
help you see commonality in the mechanism. As you study the steps, asks
yourself why doesnt the hormone just engage the enzyme directly. You will
soon realize that hormones are present in fleeting amounts and cannot be
effective at these minute levels. Rather their action depends on events that
allow the meek hormone to raise to a higher level of effectiveness and
deliver a mighty blow to the cell process in question. The meek to the
mighty helps you see how this is possible.

Initial response
Lets begin by examining a typical c-AMP-dependent hormone
response system. First we must realize that cAMP action is inside the cell
and the hormone is outside. A connection, therefore, must be made across
the membrane. The connecting point is a receptor for the hormone in close
proximity to a membrane bound enzyme, adenylcyclase (click 1).
Adenylcyclase

Hormone
receptor

GTP

cAMP
ATP

When the hormone contacts


its receptor it sets into motion
a series of reactions that
ultimately lead to the
synthesis of cAMP (click 1).
GDP
G protein

The first reaction is the exchange of GDP with GTP on G protein (click
1). This allows an active G protein to travel to adenylcyclase and stimulate
the enzyme to make cAMP from ATP (click 1). Click 1 to go on.

cAMP-dependent Protein Kinase


The next step in the reaction sequence is to activate the first kinase
enzyme, which is called cAMP-dependent protein kinase or cAPK for short. The
catalytic subunits of cAPK are held in check by regulatory subunits (click 1). But,
when cAMP is around, the regulatory subunits bind the cAMP and dissociate from
the catalytic subunits (click 1).
R

C C

+ 4 cAMP

C
C

cAMP
R cAMP
R

cAMP
cAMP

The catalytic subunit


is now free to attack
a protein target.

You should note at this stage that by raising cAMP levels through an enzyme, the
hormone has dramatically amplified its ability to elicit a response. This is the
advantage of a catalytic (one begets many) as opposed to a stoichiometric (one
begets one) response. Click 1 to go on.

Inactive
Phosphorylase
Kinase

Calmodulin

cAPK

2ATP

2ADP

Active
phosphorylase
Kinase

Catalytic site
Is any protein a target for the catalytic subunit of cAPK? No, only
kinase enzymes will be acted upon. These target enzymes, therefore, must
have some unique features. Phosphorylase kinase, for example, is composed
of 4 different subunits (click 1). The delta subunit is calmodulin, a calcium
binding protein, that regulates the activity (click 1). The gamma subunit has the
catalytic site (click 1). The enzyme is not active. To activate phosphorylase
kinase, the catalytic subunit transfers 2 PO4s from 2 ATPs to the alpha and beta
subunits (click 1). Phosphorylation at these sites renders phosphorylase kinase
active. Conversely, removing phosphate inactivates the kinase. Be alert,
therefore, to phosphatases that may exert control over the function of
phosphorylase kinases. Click 1 to go on.

Crunch Time
Now comes crunch time. What is the function of the target kinases.
The answer is they phosphorylate enzymes that control a critical steps in a
pathway. For example, phosphorylase or glycogen synthase are targets of a
protein kinase. For phosphorylase, the kinase enzyme is phosphorylase kinase.
The sequence of events is highlighted in the figure below (click 1).

Adenylcyclase

cAMP dependent
protein kinase

C C

Phosphorylase
kinase

Phosphorylase

So now you can see how a hormone external to a cell can have a profound
effect on glycogen degradation, glycogen synthesis, and other processes
whose enzymes have activities controlled by the presence or absence of
phosphate groups. Click 1 to test what you learned.

Test and Expand your Knowledge of cAMP Systems


1. Besides glucagon, can you name other hormones that elicit a cAMP
response?
Ans: epinephrine and norepinephrine
2. What name is given to a class of receptors that connect with adenylcyclase
thru G proteins?
Ans: Beta adrenergic
3. Based on the composition of phosphorylase kinase, what other factor may
be expected to stimulate the activity of the enzyme and increase glycogen
breakdown?
Ans: Calcium ion. It binds to calmodulin one of the subunits of the kinase and
activates the gamma (catalytic) subunit.
4. Supposing one hormone elicits 100 times it number of cAMP molecules.
Then 2 cAMP molecules elicits 500 times their number of active
phosphorylase kinases. Now suppose each phosphorylase kinase activates
1000 phosphorylase molecules. How many times has the single hormone
been amplified?
Ans: 25 million times. This means that one nanomole is having the same effect
as 25 millimoles of hormone.