Interactions Between Cells and the Extracellular Environment 155The polar regulatory molecule (neurotransmitter, hormone,
or paracrine regulator) doesn’t enter the cell, and so its actions
are produced by the second messenger. For example, because
the hormone epinephrine (adrenalin) uses cAMP as a second
messenger in its stimulation of the heart, these effects are actu-
ally produced by cAMP within the heart cells. Cyclic AMP
and several other second messengers are discussed in con-
junction with the action of particular hormones in chapter 11,
section 11.2.G-Proteins
Notice that, in the second step of the previous list, the bind-
ing of the polar regulatory molecule to its receptor activates
an enzyme protein in the plasma membrane indirectly. This is
because the receptor protein and the enzyme protein are in dif-
ferent locations within the plasma membrane. Thus, there has
to be something that travels in the plasma membrane between
the receptor and the enzyme, so that the enzyme can become
activated. In 1994 the Nobel Prize in Physiology or Medicine
was awarded for the discovery of the G-proteins: three protein
subunits that shuttle between receptors and different membrane
effector proteins, including specific enzymes and ion channels.
The three G-protein subunits are designated by the Greek let-
ters alpha, beta, and gamma ( a , b , and g ).
When the regulatory molecule reaches the plasma mem-
brane of its target cell and binds to its receptor, the alpha sub-
unit dissociates from the beta-gamma subunits (which stay
attached to each other). The dissociation of the alpha from
the beta-gamma subunits occurs because the alpha subunit
releases GDP (guanosine diphosphate) and binds to GTP
(guanosine triphosphate). The alpha subunit (or in some cases
the beta-gamma subunits) then moves through the membrane
and binds to the effector protein, which is an enzyme or ion
channel. This temporarily activates the enzyme or operates
(opens or closes) the ion channel. Then, the alpha subunit
hydrolyzes the GTP into GDP and P i (inorganic phosphate),
which causes the three subunits to reaggregate and move back
to the receptor protein. This cycle is illustrated in figure 6.31.
The effector protein in figure 6.31 may be an enzyme,
such as the enzyme that produces the second-messenger mol-
ecule cyclic AMP. This may be seen in the action of epineph-
rine and norepinephrine on the heart, shown in chapter 7,
figure 7.31. Or the effector protein may be an ion channel, as
can be seen in the way that acetylcholine (a neurotransmitter)
causes the heart rate to slow (shown in chapter 7, fig. 7.27).
Because there are an estimated 400 to 500 different G-protein-
coupled receptors for neurotransmitters, hormones, and para-
crine regulators (plus several hundred more G-protein-coupled
receptors producing sensations of smell and taste), there is
great diversity in their effects. Thus, specific cases are best
considered in conjunction with the nervous, sensory, and endo-
crine systems in the chapters that follow.regulatory molecules. This great diversity allows the many
regulatory molecules in the body to exert fine control over the
physiology of our tissues and organs.
These receptor proteins may be located on the outer sur-
face of the plasma membrane of the target cells, or they may be
located intracellularly in either the cytoplasm or nucleus. The
location of the receptor proteins depends on whether the regula-
tory molecule can penetrate the plasma membrane of the target
cell ( fig. 6.30 ).
If the regulatory molecule is nonpolar, it can diffuse
through the cell membrane and enter the target cell. Such
nonpolar regulatory molecules include steroid hormones,
thyroid hormones, and nitric oxide gas (a paracrine regula-
tor). In these cases, the receptor proteins are intracellular in
location. Regulatory molecules that are large or polar—such
as epinephrine (an amine hormone), acetylcholine (an amine
neurotransmitter), and insulin (a polypeptide hormone)—
cannot enter their target cells. In these cases, the recep-
tor proteins are located on the outer surface of the plasma
membrane.
Second Messengers
If a polar regulatory molecule binds to a receptor protein in
the plasma membrane, how can it influence affairs deep in the
cell? Even though the regulatory molecule doesn’t enter the
cell, it somehow has to change the activity of specific proteins,
including enzyme proteins, within the cytoplasm. This feat is
accomplished by means of intermediaries, known as second
messengers, sent into the cytoplasm from the receptor proteins
in the plasma membrane ( fig. 6.30 ).
Second messengers may be ions (most commonly Ca^2 1 )
that enter the cell from the extracellular fluid, or molecules
produced within the cell cytoplasm in response to the bind-
ing of polar regulatory molecules to their receptors in the
plasma membrane. One important second-messenger mol-
ecule is cyclic adenosine monophosphate (abbreviated
cyclic AMP, or cAMP ). The details of this regulation are
described in conjunction with neural and endocrine regula-
tion in the next several chapters (for example, see chapter 7,
fig. 7.31). However, the following general sequence of events
can be described here:
- The polar regulatory molecule binds to its receptor in the
plasma membrane. - This indirectly activates an enzyme in the plasma mem-
brane that produces cyclic AMP from its precursor, ATP,
in the cell cytoplasm. - Cyclic AMP concentrations increase, activating previ-
ously inactive enzymes in the cytoplasm. - The enzymes activated by cAMP then change the activi-
ties of the cell to produce the action of the regulatory
molecule.