Medical Physiology, 3rd Edition

Peptide Hormones

Specialized endocrine cells synthesize, store, and secrete peptide hormones

Organisms as primitive as fungi secrete proteins or peptides in an effort to respond to and affect their environment. In more complex organisms, peptide hormones play important developmental and other regulatory roles. Transcription of peptide hormones is regulated by both cis- and trans-acting elements (see p. 78). When transcription is active, the mRNA is processed in the nucleus and the capped message moves to the cytosol, where it associates with ribosomes on the rough endoplasmic reticulum. These peptides are destined for secretion because an amino-acid signal sequence (see p. 28) present near the N terminus targets the protein to the endoplasmic reticulum while the protein is still associated with the ribosome.

With minor modification, the secretory pathway illustrated in Figure 2-18 can describe the synthesis, processing, storage, and secretion of peptides by a wide variety of endocrine tissues. Once the protein is in the lumen of the endoplasmic reticulum, processing (e.g., glycosylation or further proteolytic cleavage) yields the mature, biologically active hormone. This processing occurs in a very dynamic setting. The protein is first transferred to the cis-Golgi domain, then through to the trans-Golgi domain, and finally to the membrane-bound secretory vesicle or granule in which the mature hormone is stored before secretion. This pathway is referred to as the regulated pathway of hormone synthesis because external stimuli can trigger the cell to release hormone that is stored in the secretory granule as well as to increase synthesis of additional hormone. For example, binding of GHRH to somatotrophs causes them to release GH.

A second pathway of hormone synthesis is the constitutive pathway. Here, secretion occurs more directly from the endoplasmic reticulum or vesicles formed in the cis Golgi. Secretion of hormone, both mature and partially processed, by the constitutive pathway is less responsive to secretory stimuli than is secretion by the regulated pathway.

In both the regulated and constitutive pathways, fusion of the vesicular membrane with the plasma membrane—exocytosis of the vesicular contents—is the final common pathway for hormone secretion. In general, the regulated pathway is capable of secreting much larger amounts of hormone—on demand—than is the constitutive pathway. However, even when stimulated to secrete its peptide hormone, the cell typically secretes only a very small amount of the total hormone present in the secretory granules. To maintain this secretory reserve, many endocrine cells increase the synthesis of peptide hormones in response to the same stimuli that trigger secretion.

Peptide hormones bind to cell-surface receptors and activate a variety of signal-transduction systems

Once secreted, most peptide hormones exist free in the circulation. As noted above, this lack of binding proteins contrasts with the situation for steroid and thyroid hormones, which circulate bound to plasma proteins. IGF-1 and IGF-2 are an exception to this rule: at least six plasma proteins bind these peptide growth factors.

While traversing the circulation, peptide hormones encounter receptors on the surface of target cells. These receptors are intrinsic membrane proteins that bind the hormone with very high affinity (typically, KD ranges from 10−8 to 10−12 M). Examples of several types of peptide hormone receptors are shown in Figure 47-4. Each of these receptors has already been introduced in Chapter 3. The primary sequence of most peptide hormone receptors is known from molecular cloning, mutant receptors have been synthesized, and the properties of native and mutant receptors have been compared to assess primary structural requirements for receptor function. Despite this elegant work, too little information is available on the three-dimensional structure of these membrane proteins for us to know just how the message that a hormone has bound to the receptor is transmitted to the internal surface of the cell membrane. However, regardless of the details, occupancy of the receptor can activate many different intracellular signal-transduction systems (Table 47-3) that transfer the signal of cell activation from the internal surface of the membrane to intracellular targets. The receptor provides the link between a specific extracellular hormone and the activation of a specific signal-transduction system. We discussed each of these signal-transduction systems in Chapter 3. Here, we briefly review the various signal-transduction systems through which peptide hormones act.


FIGURE 47-4 Receptors and downstream effectors for peptide hormones. AC, adenylyl cyclase.

TABLE 47-3

Peptide Hormones and Their Signal-Transduction Pathways






Coupled to Gαs

Adenylyl cyclase



Coupled to Gαi

Adenylyl cyclase (inhibited)



Coupled to Gαq


IP3 and DAG


Coupled to Gi/Go


Arachidonic acid metabolites


Guanylyl cyclase

Guanylyl cyclase


Insulin, IGF-1, IGF-2, EGF, PDGF

Tyrosine kinase

Tyrosine kinase


GH, erythropoietin, LIF

Associated with tyrosine kinase

JAK/STAT family of tyrosine kinases


ANG II, angiotensin II; ANP, atrial natriuretic peptide; EGF, epidermal growth factor; LIF, leukemia inhibitory factor; STAT, signal transducer and activator of transcription.

G Proteins Coupled to Adenylyl Cyclase

cAMP, the prototypical second messenger, was discovered during an investigation of the action of glucagon on glycogenolysis in the liver. In addition to playing a role in hormone action, cAMP is involved in such diverse processes as lymphocyte activation, mast cell degranulation, and even slime mold aggregation.

As summarized in Figure 47-4A, binding of the appropriate hormone (e.g., PTH) to its receptor initiates a cascade of events (see pp. 56–57): (1) activation of a heterotrimeric G protein (αs or αi); (2) activation (by αs) or inhibition (by αi) of a membrane-bound adenylyl cyclase; (3) formation of intracellular cAMP from ATP, catalyzed by adenylyl cyclase; (4) binding of cAMP to the enzyme protein kinase A (PKA); (5) separation of the two catalytic subunits of PKA from the two regulatory subunits; (6) phosphorylation of serine and threonine residues on a variety of cellular enzymes and other proteins by the free catalytic subunits of PKA that are no longer restrained; and (7) modification of cellular function by these phosphorylations. The activation is terminated in two ways. First, phosphodiesterases in the cell degrade cAMP. Second, serine/threonine-specific phosphoprotein phosphatases can dephosphorylate enzymes and proteins that had previously been phosphorylated by PKA (Box 47-2).

Box 47-2


Inasmuch as G proteins are part of the signaling system involved in large numbers of hormone responses, molecular alterations in G proteins could be expected to affect a number of signaling systems. In the disorder pseudohypoparathyroidism, the key defect is an abnormality in a stimulatory α subunit (αs) of a heterotrimeric G protein. The result is an impairment in the ability of PTH to regulate body calcium and phosphorus homeostasis (see pp. 1058–1063). Patients with this disorder have a low serum calcium level and high serum phosphate level, just like patients whose parathyroid glands have been surgically removed. However, patients with pseudohypoparathyroidism have increased circulating concentrations of PTH; the hormone simply cannot act normally on its target tissue, hence the term pseudohypoparathyroidism. These individuals also have an increased risk of hypothyroidism, as well as of gonadal dysfunction. These additional endocrine deficiencies arise from the same defect in signaling.

G Proteins Coupled to Phospholipase C

As summarized in Figure 47-4B, binding of the appropriate peptide hormone (e.g., AVP) to its receptor initiates the following cascade of events (see pp. 58–61): (1) activation of Gαq; (2) activation of a membrane-bound phospholipase C (PLC); and (3) cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) by this PLC, with the generation of two signaling molecules, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).

The IP3 fork of the pathway includes (4a) binding of IP3 to a receptor on the cytosolic surface of the endoplasmic reticulum; (5a) release of Ca2+ from internal stores, which causes [Ca2+]i to rise by several-fold; and (6a) activation of Ca2+-dependent kinases (e.g., Ca2+-calmodulin–dependent protein kinases, protein kinase C [PKC]) by the increases in [Ca2+]i.

The DAG fork of the pathway includes (4b) allosteric activation of PKC by DAG (the activity of this enzyme is also stimulated by the increased [Ca2+]i); and (5b) phosphorylation of a variety of proteins by PKC, which is activated in the plane of the cell membrane. An example of a hormone whose actions are in part mediated by DAG is TSH.

G Proteins Coupled to Phospholipase A2

As summarized in Figure 47-4C, some peptide hormones (e.g., TRH) activate phospholipase A2 (PLA2) through the following cascade (see pp. 58–61): (1) activation of Gαq or Gα11, (2) stimulation of membrane-bound PLA2 by the activated Gα, (3) cleavage of membrane phospholipids by PLA2 to produce lysophospholipid and arachidonic acid, and (4) conversion—by several enzymes—of arachidonic acid into a variety of biologically active eicosanoids (e.g., prostaglandins, prostacyclins, thromboxanes, and leukotrienes).

Guanylyl Cyclase

Other peptide hormones (e.g., atrial natriuretic peptide) bind to a receptor (see Fig. 47-4D) that is itself a guanylyl cyclase that converts cytoplasmic GTP to cGMP (see pp. 66–67). In turn, cGMP can activate cGMP-dependent kinases, phosphatases, or ion channels.

Receptor Tyrosine Kinases

For some peptide hormones, notably insulin and IGF-1 and IGF-2, the hormone receptor (see Fig. 47-4E) itself possesses tyrosine kinase activity (see pp. 68–70). This is also a property of other growth factors, including PDGF and epidermal growth factor. Occupancy of the receptor by the appropriate hormone increases kinase activity. For the insulin and IGF-1 receptor, as well as for others, this kinase autophosphorylates tyrosines within the hormone receptor, as well as substrates within the cytosol, thus initiating a cascade of phosphorylation reactions.

Tyrosine Kinase–Associated Receptors

Some peptide hormones (e.g., GH) bind to a receptor that, when occupied, activates a cytoplasmic tyrosine kinase (see Fig. 47-4F), such as a member of the JAK (Janus kinase, or just another kinase) family of kinases (see pp. 70–71). As for the receptor tyrosine kinases, activation of these receptor-associated kinases initiates a cascade of phosphorylation reactions.