Human Physiology, 14th edition (2016)

330 Chapter 11

In the case of many growth factors, the binding of the ligand

to its receptor causes the receptors to form dimers that allow one

member to phosphorylate the other in a process of autophos-

phorylation. This activates the tyrosine kinase portion on the

cytoplasmic side of the receptor. However, the insulin receptor

is already a homodimer of two half-receptors (each composed

of two polypeptide chains), which is bound together by disulfide

bonds (chapter 2, see fig. 2.29) even before it binds to insulin.

The insulin receptor forms the shape of an inverted “V” that has

an insulin-binding site on its extracellular surface ( fig.  11.11 ).

Recent observations demonstrate that a single insulin molecule

binds to the sites and causes a portion of the polypeptide to

move. This conformational change results in autophosphoryla-

tion of the receptor, activating its tyrosine kinase activity.

The activated insulin receptor then phosphorylates insulin

receptor substrate proteins, which provide an enzymatic docking

station that activates a variety of other signaling molecules. These

signaling molecules cause the insertion of transport carrier proteins

for glucose into the plasma membrane (see fig. 11.30 ), and so pro-

mote the uptake of plasma glucose into tissue cells. In this way,

insulin promotes the lowering of the plasma glucose concentra-

tion. Some signaling molecules activate other second-messenger

systems within the target cells, allowing insulin and growth factors

to regulate different aspects of the metabolism of their target cells.

Figure 11.11 The receptor for insulin. The receptor is a homodimer of two half-receptors bound together to form
an inverted “V.” There are two insulin-binding sites on the extracellular side of the receptor, and the binding of insulin causes a
conformational change that results in autophosphorylation of the receptor. This activates its tyrosine kinase activity, leading to
phosphorylation of signaling molecules that result in the effects of insulin on its target cells.

Insulin

receptor

Insulin

Extracellular

fluid

Cytoplasm

P P

P P

P

ADP

ATP

ADP

ATP

ADP

ATP

ADP

ATP

P

Two half-receptors form

dimer prior to insulin

binding

1. Insulin binding causes
   autophosphorylation of
   receptor

2.

Active tyrosine kinase

of receptor phosphorylates

signaling molecule

3.

Active signaling molecule

causes cascade of effects

4.

Glucose uptake and

anabolic reactions

(a) (b) (c)

PP

1. The hormone binds to its receptor on the outer surface of the
   target cell’s plasma membrane.


2. Hormone-receptor interaction stimulates the activity of a
   membrane enzyme, phospholipase C.


3. Activated phospholipase C catalyzes the conversion
   of particular phospholipids in the membrane to inositol
   triphosphate (IP 3 ) and another derivative, diacylglycerol.


4. Inositol triphosphate enters the cytoplasm and diffuses to the
   endoplasmic reticulum, where it binds to its receptor proteins
   and causes the opening of Ca^21 channels.


5. Since the endoplasmic reticulum accumulates Ca^21 by active
   transport, there exists a steep Ca^21 concentration gradient
   favoring the diffusion of Ca^21 into the cytoplasm.


6. Ca^21 that enters the cytoplasm binds to and activates a protein
   called calmodulin.


7. Activated calmodulin, in turn, activates protein kinase, which
   phosphorylates other enzyme proteins.


8. Altered enzyme activity mediates the target cell’s response to
   the hormone.

Table 11.5 | Sequence of Events Involving
the Ca^21 Second-Messenger System