722

chapter 30

Endocrine Metabolism I: Introduction

FIGURE 30-11

Mechanism of prolactin receptor activation. Activation of prolactin receptor consists of ligand-induced sequential

receptor homodimerization driven by the two binding sites of prolactin. In the intracellular domain of the homodimer of

the ligand-receptor complex, a tyrosine kinase [known as Janus kinase 2 (Jak-2)] is activated. Jak-2 kinase causes

autophosphorylation and phosphorylation of the receptor. [Reproduced with permission from M. E. Freeman,

B. Kanyicska, A. Lerant, and G. Nagy,

Physiological R eviews

80, 1530 (2000).]

activities

that are

unrelated

to glucose

uptake

and

utilization.

The IGF-I receptor is an

otifiy

heterotetramer that is

structurally similar to the insulin receptor but is coded

for by a different, single-copy gene located within bands

q25-26 of chromosome 15. Like the insulin receptor, with

which it shares 50-60% sequence homology, the IGF-I

receptor has a cysteine-rich domain in the

a

subunit

for ligand binding and a tyrosine kinase domain in the

/6

subunit that catalyzes transphosphorylation of contralat-

eral /3-subunit sites. The receptor has highest affinity for

IGF-I, a lesser affinity for IGF-II (about 2- to 15-fold less),

and low affinity for insulin (about ~

1 0 0

- to

1 0 0 0

-fold

less) due to the absence of insulin-binding determinants

in the

a

subunit.

Receptors for Growth Hormone and Prolactin

Growth hormone (GH) and prolactin (PRL) belong to

the “helix bundle peptide” (HBP) hormone family, which

includes human placental lactogen (hPL), erythropoietin

(EPO), and many interleukins and cytokines. All members

of this family have similar mechanisms of action; they

utilize membrane receptors that are straight-chain glyco-

proteins with extracellular, transmembrane and intracel-

lular domains. The membrane receptors for this group of

hormones when bound with their respective receptors un-

dergo dimerization. Each dimerized receptor is bound to

one molecule of hormone. The intracellular events of the

ligand-mediated activation of the receptor consists of acti-

vation of a constitutively associated tyrosine kinase known

as Janus kinase 2 (Jak-2). Jak-2 kinase transphosphory-

lates itself and phosphorylâtes the intracellular domains

of the receptor. Figure 30-11 illustrates the mechanism

of prolactin receptor activation. The signal transduction

pathways for GH and PRL are discussed in Chapter 31.

30.6 Organization of the Endocrine System

The nervous and endocrine systems function in a coordi-

nated manner to promote growth, homeostasis, and repro-

ductive competence. The need to rapidly adjust physio-

logical processes in response to impending disturbances

in homeostasis is met by the nervous system, while the

endocrine system effects the more prolonged, fine-tuned

adjustments. Together, they effect appropriate organismic

adaptation. Some interdependence also exists between the

two systems. The nervous system, for example, relies

heavily on a continuous supply of glucose, the circulat-

ing levels of which are under multiple hormonal control,

while maturation of the nervous system is regulated by thy-

roid hormone, and maintenance of mental acuity in adults

depends on the availability of both thyroid hormone and

glucocorticoids. On the other hand, hormone production is

generally dependent on the nervous system, albeit to vary-

ing extents. The synthesis of insulin, glucagon, calcitonin,

parathyroid hormone, and aldosterone appears to require

little or no neural regulation, whereas that of the hypotha-

lamic peptides and adrenal medullary hormones is totally

dependent on it. It may be significant that those hormones

which are relatively independent of neural control serve