Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 2Overview of Cellular Physiology in Medical Physiology 59

depends on the constancy of this fluid, it is not surprising that
in multicellular animals, an immense number of regulatory
mechanisms have evolved to maintain it. To describe “the var-
ious physiologic arrangements which serve to restore the nor-
mal state, once it has been disturbed,” W.B. Cannon coined
the term homeostasis. The buffering properties of the body
fluids and the renal and respiratory adjustments to the pres-
ence of excess acid or alkali are examples of homeostatic

mechanisms. There are countless other examples, and a large

part of physiology is concerned with regulatory mechanisms

that act to maintain the constancy of the internal environ-

ment. Many of these regulatory mechanisms operate on the

principle of negative feedback; deviations from a given normal

set point are detected by a sensor, and signals from the sensor

trigger compensatory changes that continue until the set point

is again reached.

CLINICAL BOX 2–3

Receptor & G Protein Diseases

Many diseases are being traced to mutations in the genes

for receptors. For example, loss-of-function receptor muta-

tions that cause disease have been reported for the 1,25-

dihydroxycholecalciferol receptor and the insulin receptor.

Certain other diseases are caused by production of anti-

bodies against receptors. Thus, antibodies against thyroid-

stimulating hormone (TSH) receptors cause Graves’ dis-

ease, and antibodies against nicotinic acetylcholine recep-

tors cause myasthenia gravis.

An example of loss of function of a receptor is the type of

nephrogenic diabetes insipidus that is due to loss of the

ability of mutated V 2 vasopressin receptors to mediate con-

centration of the urine. Mutant receptors can gain as well

as lose function. A gain-of-function mutation of the Ca2+

receptor causes excess inhibition of parathyroid hormone

secretion and familial hypercalciuric hypocalcemia. G

proteins can also undergo loss-of-function or gain-of-func-

tion mutations that cause disease (Table 2–6), In one form

of pseudohypoparathyroidism, a mutated Gsα fails to re-

spond to parathyroid hormone, producing the symptoms

of hypoparathyroidism without any decline in circulating

parathyroid hormone. Testotoxicosis is an interesting dis-

ease that combines gain and loss of function. In this condi-

tion, an activating mutation of Gsα causes excess testoster-

one secretion and prepubertal sexual maturation. However,

this mutation is temperature-sensitive and is active only

at the relatively low temperature of the testes (33 °C). At

37 °C, the normal temperature of the rest of the body, it is

replaced by loss of function, with the production of hypo-

parathyroidism and decreased responsiveness to TSH. A

different activating mutation in Gsα is associated with the

rough-bordered areas of skin pigmentation and hypercorti-

solism of the McCune–Albright syndrome. This mutation

occurs during fetal development, creating a mosaic of nor-

mal and abnormal cells. A third mutation in Gsα reduces its

intrinsic GTPase activity. As a result, it is much more active

than normal, and excess cAMP is produced. This causes hy-

perplasia and eventually neoplasia in somatotrope cells of

the anterior pituitary. Forty percent of somatotrope tumors

causing acromegaly have cells containing a somatic muta-

tion of this type.

TABLE 2–6 Examples of abnormalities caused by

loss- or gain-of-function mutations of heterotrimeric

G protein-coupled receptors and G proteins.

Site

Type of

Mutation Disease

Receptor

Cone opsins Loss Color blindness

Rhodopsin Loss Congenital night blindness; two

forms of retinitis pigmentosa

V 2 vasopressin Loss X-linked nephrogenic diabetes

insipidus

ACTH Loss Familial glucocorticoid deficiency

LH Gain Familial male precocious puberty

TSH Gain Familial nonautoimmune hyperthy-

roidism

TSH Loss Familial hypothyroidism

Ca2+ Gain Familial hypercalciuric hypocalcemia

Thromboxane

A 2

Loss Congenital bleeding

Endothelin B Loss Hirschsprung disease

G protein

Gs α Loss Pseudohypothyroidism type 1a

Gs α Gain/loss Testotoxicosis

Gs α Gain

(mosaic)

McCune–Albright syndrome

Gs α Gain Somatotroph adenomas with acro-

megaly

Gi α Gain Ovarian and adrenocortical tumors

Modified from Lem J: Diseases of G-protein-coupled signal transduc-

tion pathways: The mammalian visual system as a model. Semin Neuro-

sci 1998;9:232.