Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 2Overview of Cellular Physiology in Medical Physiology 51

chemical messengers exert their intracellular effects are sum-
marized in Table 2–3. Ligands such as acetylcholine bind di-
rectly to ion channels in the cell membrane, changing their
conductance. Thyroid and steroid hormones, 1,25-dihydroxy-
cholecalciferol, and retinoids enter cells and act on one or an-
other member of a family of structurally related cytoplasmic or
nuclear receptors. The activated receptor binds to DNA and in-
creases transcription of selected mRNAs. Many other ligands in
the ECF bind to receptors on the surface of cells and trigger the
release of intracellular mediators such as cAMP, IP 3 , and DAG
that initiate changes in cell function. Consequently, the extra-
cellular ligands are called “first messengers” and the intra-
cellular mediators are called “second messengers.” Second
messengers bring about many short-term changes in cell func-
tion by altering enzyme function, triggering exocytosis, and so
on, but they also can lead to the alteration of transcription of
various genes. A variety of enzymatic changes, protein–protein
interactions or second messenger changes can be activated
within a cell in an orderly fashion following receptor recogni-
tion of the primary messenger. The resulting cell signaling
pathway provides amplification of the primary signal and dis-
tribution of the signal to appropriate targets within the cell. Ex-
tensive cell signaling pathways also provide opportunities for
feedback and regulation that can fine tune the signal for the cor-
rect physiological response by the cell.
The most predominant posttranslation modification of pro-
teins, phosphorylation, is a common theme in cell signaling

pathways. Cellular phosphorylation is under the control of two

groups of proteins: kinases, enzymes that catalyze the phos-

phorylation of tyrosine or serine and threonine residues in pro-

teins (or in some cases, in lipids); and phosphatases, proteins

that remove phosphates from proteins (or lipids). Some of the

larger receptor families are themselves kinases. Tyrosine kinase

receptors initiate phosphorylation on tyrosine residues on com-

plementary receptors following ligand binding. Serine/threo-

nine kinase receptors initiate phosphorylation on serines or

threonines in complementary receptors following ligand bind-

ing. Cytokine receptors are directly associated with a group of

protein kinases that are activated following cytokine binding.

Alternatively, second messengers changes can lead to phos-

phorylation further downstream in the signaling pathway.

More than 300 protein kinases have been described. Some of

the principal ones that are important in mammalian cell signal-

ing are summarized in Table 2–4. In general, addition of phos-

phate groups changes the conformation of the proteins, altering

their functions and consequently the functions of the cell. The

close relationship between phosphorylation and dephosphory-

lation of cellular proteins allows for a temporal control of acti-

vation of cell signaling pathways. This is sometimes referred to

as a “phosphate timer.”

STIMULATION OF TRANSCRIPTION

The activation of transcription, and subsequent translation,

is a common outcome of cellular signaling. There are three

TABLE 2–3 Common mechanisms by which
chemical messengers in the ECF bring about
changes in cell function.

Mechanism Examples

Open or close ion channels in cell

membrane

Acetylcholine on nicotinic cholin-

ergic receptor; norepinephrine

on K+ channel in the heart

Act via cytoplasmic or nuclear re-

ceptors to increase transcription

of selected mRNAs

Thyroid hormones, retinoic acid,

steroid hormones

Activate phospholipase C with in-

tracellular production of DAG, IP 3 ,

and other inositol phosphates

Angiotensin II, norepinephrine

via α 1 -adrenergic receptor, vaso-

pressin via V 1 receptor

Activate or inhibit adenylyl

cyclase, causing increased or

decreased intracellular

production of cAMP

Norepinephrine via β 1 -adrener-

gic receptor (increased cAMP);

norepinephrine via α 2 -adrener-

gic receptor (decreased cAMP)

Increase cGMP in cell Atrial natriuretic peptide; nitric

oxide

Increase tyrosine kinase activity

of cytoplasmic portions of trans-

membrane receptors

Insulin, epidermal growth factor

(EGF), platelet-derived growth

factor (PDGF), monocyte colony-

stimulating factor (M-CSF)

Increase serine or threonine

kinase activity

TGFβ, activin, inhibin

TABLE 2–4 Sample protein kinases.

Phosphorylate serine or threonine residues, or both

Calmodulin-dependent

Myosin light-chain kinase

Phosphorylase kinase

Ca2+/calmodulin kinase I

Ca2+/calmodulin kinase II

Ca2+/calmodulin kinase III

Calcium-phospholipid-dependent

Protein kinase C (seven subspecies)

Cyclic nucleotide-dependent

cAMP-dependent kinase (protein kinase A; two subspecies)

cGMP-dependent kinase

Phosphorylate tyrosine residues

Insulin receptor, EGF receptor, PDGF receptor, and

M-CSF receptor