Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 2Overview of Cellular Physiology in Medical Physiology 57

its GTPase activity, producing prolonged stimulation of aden-
ylyl cyclase. Pertussis toxin catalyzes ADP-ribosylation of a
cysteine residue near the carboxyl terminal of the α subunit of
Gi. This inhibits the function of Gi. In addition to the implica-
tions of these alterations in disease, both toxins are used for
fundamental research on G protein function. The drug for-
skolin also stimulates adenylyl cyclase activity by a direct
action on the enzyme.

GUANYLYL CYCLASE

Another cyclic nucleotide of physiologic importance is cyclic
guanosine monophosphate (cyclic GMP or cGMP). Cyclic
GMP is important in vision in both rod and cone cells. In ad-
dition, there are cGMP-regulated ion channels, and cGMP ac-
tivates cGMP-dependent kinase, producing a number of
physiologic effects.
Guanylyl cyclases are a family of enzymes that catalyze the
formation of cGMP. They exist in two forms (Figure 2–29).
One form has an extracellular amino terminal domain that is
a receptor, a single transmembrane domain, and a cytoplas-
mic portion with guanylyl cyclase catalytic activity. Three
such guanylyl cyclases have been characterized. Two are
receptors for atrial natriuretic peptide (ANP; also known as
atrial natriuretic factor), and a third binds an Escherichia coli
enterotoxin and the gastrointestinal polypeptide guanylin.
The other form of guanylyl cyclase is soluble, contains heme,
and is not bound to the membrane. There appear to be several
isoforms of the intracellular enzyme. They are activated by
nitric oxide (NO) and NO-containing compounds.

GROWTH FACTORS

Growth factors have become increasingly important in many

different aspects of physiology. They are polypeptides and

proteins that are conveniently divided into three groups. One

group is made up of agents that foster the multiplication or de-

velopment of various types of cells; nerve growth factor

(NGF), insulin-like growth factor I (IGF-I), activins and in-

hibins, and epidermal growth factor (EGF) are examples.

More than 20 have been described. The cytokines are a second

group. These factors are produced by macrophages and lym-

phocytes, as well as other cells, and are important in regulation

of the immune system (see Chapter 3). Again, more than 20

have been described. The third group is made up of the colo-

ny-stimulating factors that regulate proliferation and matura-

tion of red and white blood cells.

Receptors for EGF, platelet-derived growth factor (PDGF),

and many of the other factors that foster cell multiplication

and growth have a single membrane-spanning domain with

an intracellular tyrosine kinase domain (Figure 2–29). When

ligand binds to a tyrosine kinase receptor, it first causes a

dimerization of two similar receptors. The dimerization

results in partial activation of the intracellular tyrosine kinase

domains and a cross-phosphorylation to fully activate each

other. One of the pathways activated by phosphorylation

leads, through the small G protein Ras, to MAP kinases, and

eventually to the production of transcription factors in the

nucleus that alter gene expression (Figure 2–30).

Receptors for cytokines and colony-stimulating factors differ

from the other growth factors in that most of them do not have

tyrosine kinase domains in their cytoplasmic portions and

FIGURE 2–28 The cAMP system. Activation of adenylyl cyclase
catalyzes the conversion of ATP to cAMP. Cyclic AMP activates protein
kinase A, which phosphorylates proteins, producing physiologic ef-
fects. Stimulatory ligands bind to stimulatory receptors and activate
adenylyl cyclase via Gs. Inhibitory ligands inhibit adenylyl cyclase via
inhibitory receptors and Gi. ISF, interstitial fluid.

Stimulatory

receptor

Adenylyl

cyclase

Inhibitory

receptor

Protein kinase A

ISF

Phosphoproteins

Cytoplasm

Physiologic effects

GS Gi

ATP CAMP

PDE

5' AMP

α

β

γ α

β

γ

FIGURE 2–29 Diagrammatic representation of guanylyl

cyclases, tyrosine kinases, and tyrosine phosphatases. ANP, atrial

natriuretic peptide; C, cytoplasm; cyc, guanylyl cyclase domain; EGF,

epidermal growth factor; ISF, interstitial fluid; M, cell membrane; PDGF,

platelet-derived growth factor; PTK, tyrosine kinase domain; PTP, ty-

rosine phosphatase domain; ST, E. coli enterotoxin. (Modified from

Koesling D, Böhme E, Schultz G: Guanylyl cyclases, a growing family of signal

transducing enzymes. FASEB J 1991;5:2785.)

ANP

ISF

M

C

PTK

ST

NH 2 NH 2

NH 2

NH 2

NH 2

NH 2

cyc

cyc

cyc

COOH

COOH

COOHCOOH

PTP

PTP

PTK PTP

PTK

Guanylyl

cyclases

Tyrosine

kinases

Tyrosine

phosphatases

COOHCOOH

COOH

PDGF

EGF