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Polypeptide Hormones
Panhypopituitarism: Malfunction of the Hypothalamus–Pituitary–End Organ Axis
The pituitary is the source of several hormones that control many essential terminal hormonal functions. These include signals from the anterior pituitary that governs the stress hormone, cortisol from the adrenal cortex, the thyroid hormone from the thyroid gland, growth hormone (GH) from the anterior pituitary, sex hormones from the gonads of both male and female, the reabsorption of water from the kidney as well as milk secretion from the mammary gland and other actions. A loss or diminution of all of these functions is called “ panhypopituitarism .” A loss of one of these functions is called “ hypopituitarism .” Thus panhypopituitarism is an appropriate clinical example to introduce the subject of polypeptide hormones.
The hormones of the anterior pituitary hormones are: the adrenocorticotropic hormone, ACTH; thyroid-stimulating hormone (or thyrotropin), TSH; GH; the gonadotrophic hormones: luteinizing hormone, LH; and follicle-stimulating hormone, FSH. The hormones of the posterior pituitary are the antidiuretic hormone, ADH (or vasopressin, VP), for water reabsorption in the kidney, and oxytocin, OT (for muscular contraction in the secretion of milk in the mammary gland and other functions). The stimulus for the secretion of each of these hormones from the anterior pituitary comes from releasing hormones in the hypothalamus that are transported to the appropriate secretory cells of the anterior pituitary (corticotroph for ACTH; thyrotroph for TSH; somatotroph for GH; and gonadotroph for LH and FSH). The “troph” ending translates to a growth stimulus for the end organ secretory cell and the ending, “trope,” is also used that translates to causing a change in the end organ cell (e.g., thyrotroph and thyrotrope; the terms can be used interchangeably).
Incoming electrical or chemical signals to a specific region of the hypothalamus will cause a target neuron to secrete a releasing hormone specific to that neuron. If the stimulation is to a neuron secreting TRH (the thyrotropin-releasing hormone), it would be labeled a thyrotropin ergic neuron ( ergic referring to the ability of that specific neuron to synthesize and secrete TRH). The releasing hormones are corticotropic-releasing hormone , CRH (for the release of ACTH from the corticotropic cell of the anterior pituitary); thyrotropin-releasing hormone , TRH (for the release of TSH from the thyrotrope of the anterior pituitary); GH-releasing hormone , GHRH (for the release of GH from the somatotrope of the anterior pituitary); and gonadotropin-releasing hormone , GnRH (for the release of LH and FSH from the gonadotrope of the anterior pituitary). LH and FSH are synthesized in the same cell (gonadotrope) and are released together although they are packaged separately inside the cell.
ADH/arginine VP (AVP) is formed in a hypothalamic neuron [ vasopressinergic (VPergic) neuron ] and is secreted in response to a depletion of blood volume (or by certain drugs) along the axon of the secreting cell all the way to the posterior pituitary where it is released. OT is formed in an oxytocinergic (OTergic) (magnocellular) neuron of the paraventricular and supraoptic regions of the hypothalamus and is transported through long axons to the posterior pituitary where it is secreted. One signal to the OTergic neuron is stimulation of the pregnant mother’s nipple by the feeding infant. OT release also can be stimulated by estrogen and by drugs.
The releasing hormones only can reach the pituitary through a fragile stalk connecting the hypothalamus to the pituitary in a closed portal system. The narrow closed portal system carrying the releasing hormones from the hypothalamus to the anterior or posterior pituitary is enveloped by the delicate (narrow) stalk. The releasing hormones do not enter the general circulation but are confined to the portal circulation, and these hormones have a very short half-life on the order of a few minutes. The releasing hormones bind to cognate (bearing a structural relationship; in this case the structure of the releasing hormone to the binding site of the receptor) receptors in the cell membrane of the target anterior pituitary cell ( CRH binds to its receptor on the corticotropic cell of the anterior pituitary; the other releasing hormones bind to their receptors on their respective target cells in the pituitary). Panhypopituitarism can occur when the fragile stalk is severed through head trauma (e.g., an automobile accident or impacting the skull with a heavy object). When the stalk is damaged, the blood supply connecting the hypothalamus to the pituitary is disrupted, leading to an infarction of the anterior pituitary. In this case the releasing hormones do not reach the pituitary and a deficiency of the pituitary hormones begins to take place in a sequence that depends on the amounts of the native pituitary hormones that remain in cellular storage.
A picture of the hypothalamus, the stalk, and the pituitary is shown in Fig. 15.1 .
The target pituitary cell responds to the activation of the releasing hormone receptor through binding the releasing hormone and transducing the signal to affect biochemical changes in the cell leading to changes in transcription (activation of the gene for the respective pituitary hormone leading to resynthesis of the hormone) and the release from the cell of the target pituitary hormone (e.g., ACTH from receptor binding of CRH and TSH from receptor binding of TRH ). The biochemical changes in the different target cells usually consist of an increase of cyclic adenosine monophosphate (cAMP) or a stimulation of inositol trisphosphate (IP3) , or both. The pituitary hormone is released into the general circulation through thin areas ( fenestrations ) in the vessels at the bottom of the pituitary gland.
Traumatic brain injury occurs at a frequency of about two million people per year in the United States. About 80,000 of these have neuroendocrine disorders . Additionally, 50% of people with traumatic brain injury had neuroendocrine disorder that was discovered postmortem (problem undiagnosed while they were alive). There may be as many as 6.5 million people alive with consequences of this kind of injury. Symptoms of panhypopituitarism do not manifest for weeks or months following brain injury, until the effective supply of hormones has been used up. This condition is signaled by decreased vital signs and malaise with lethargy, slow heart rate, hypothermia, and sometimes with hypotension with low blood sodium. The decreased blood levels of the end organ hormones, cortisol (this hormone is essential for life), testosterone , triiodothyronine (T3) , tetraiodothyronine ( thyroxine, T4 ), and the pituitary hormone, thyroid-stimulating hormone ( TSH ), are confirmatory.
When congenital at birth, panhypopituitarism can occur in childhood as a result of poor development in the midline brain structure ( septum pellucidum ). Sometimes, tumors of the hypothalamic–pituitary region arise, of which childhood craniopharyngioma is an example. GH , the driver of stature and growth rate, is often most affected in childhood panhypopituitarism. A deficiency of TSH from the anterior pituitary leads to central hypothyroidism. The loss of the gonadotropic hormones, LH and FSH , is not visualized until puberty when the development of breasts and menstrual cycles in the female are affected. Ultrasound can detect the abnormality in females. In males the enlargement of the penis and testicles at puberty is interfered. Decreased availability of the ADH or VP from the posterior pituitary leads to diabetes insipidus with excessive urination.
During pregnancy, hypopituitarism can occur. Often as a result of profound blood loss during and following childbirth, known as Sheehan’s syndrome . Blood loss can precipitate the death of anterior pituitary cells. There is a chronic form of this syndrome that can become diagnosed months or years following childbirth, and a more rare form of the syndrome appears shortly after delivery. Autoimmune antibodies to the pituitary have been reported in some cases of Sheehan’s syndrome. In most cases, panhypopituitarism is treated by replacement of the end organ hormones . In some cases, surgery is required to remove a tumor.
A male adult, for example, has panhypopituitarism as a result of a catastrophic automobile accident. The hormones of his anterior pituitary are low due to a severed stalk, so that the releasing hormones of the hypothalamus are not reaching their target receptors on the cells of the pituitary. TSH is low so that the end organ hormones of the thyroid, T3 and T4 , are also low because there is lacking stimulation by TSH . As a result of the low thyroid hormones, there is little or no negative feedback by T3 and T4 on the hypothalamus (as we shall see later) so that the level of TRH is increased (without stimulation of the anterior pituitary thyrotrope). Because of the lack of effective GHRH , there is a paucity of somatotropin and a consequent lack of GH secretion from the somatotrope of the anterior pituitary. This deficiency causes low blood glucose (as we shall see later on) and if the problem started in boyhood, he might be a victim of dwarfism . Because the availability of CRH is low or lacking altogether, circulating ACTH is low and, therefore, the secretion of cortisol from the adrenal cortex is also low or nearly absent. This causes low blood glucose (to be explained later) and a lack of negative feedback to the hypothalamus resulting in increased CRH. Because cortisol is a key hormone for stress adaptation, it is essential that it be replaced (usually orally) to prevent death resulting in failure to adapt to extreme stress or shock as in a catastrophic accident of some sort. The gonadotropic hormones of the anterior pituitary are also low because GnRH is not reaching the gonadotropes of the anterior pituitary. Low FSH results in decreased production of sperm, and low LH results in decreased testosterone levels (as will be seen later on). Decreased circulating testosterone lowers the negative feedback to the hypothalamus and increased secretion of GnRH (although it would not be reaching the gonadotropes). Decreased ADH (VP) could result in diabetes insipidus with resulting increased urinary output. Decreased prolactin (PRL) would have little consequence for the male. It is a challenging situation for the endocrinologist to control because the end organ hormones have to be correctly titrated and, in the case of cortisol, the problem for the patient is that he/she must be able to predict stressful situations to adjust the dose of cortisol (or cortisol-like drug). Accidents could still be a dangerous and a life-threatening situation for the patient with panhypopituitarism.
One clinical test is to inject a specific releasing hormone. If there is a response of the appropriate anterior pituitary hormone, then one can conclude that the problem resides in the hypothalamus. If the anterior pituitary does not respond to the releasing hormone, then the problem (such as a tumor) may reside at the pituitary.
A tumor of the pituitary can also secrete (ectopically) an excess of a pituitary hormone. Thus if the production of GH by the tumor, for example, is very high, it would cause a pronounced increase in blood glucose and would increase the growth of soft connective tissues, causing enlargement of the nose, fingers, and possibly compressing nerves in the adult (symptoms of giantism ).
Hormonal Signaling Pathways
The releasing hormones from the hypothalamus travel down the long axons of the particular releasing hormonergic neuron to the vicinity of the portal circulation of the stalk in which the hormone is transported to the specific cell of the anterior pituitary. In the case of hormone of the posterior pituitary, the neuron in the hypothalamus that becomes excited moves the hormone (e.g., ADH) down a long axon of the same cell to the vicinity of the end of the small vessels in the posterior pituitary. The releasing hormones are confined to the portal circulation of the stalk that is composed of a very small volume of blood. Accordingly, the concentration of a releasing hormone, in any event where the hormone is released from the hypothalamic neuron, is very small on the order of nanograms (ng; 10 −9 g or less). In the closed portal circulation of the stalk, the releasing hormone must be transported to its receptor on the cell membrane of the tropic cell of the anterior pituitary. The half-life of the releasing hormone is of the order of a few minutes so that a single event is short-lived. The releasing hormone is rather quickly inactivated in the closed portal circulation by resident enzymes that either cleave the releasing hormone or remove its C-terminal amide group (in those releasing hormones that contain a C-terminal amide, this substituent is essential for activity) accounting for the short half-life. The latter enzyme is an amidase . A list of the releasing hormones of the hypothalamus is presented in Table 15.1 .
Table 15.1
Releasing Hormones of the Hypothalamus.
| Hormone | Number of AA Residues | Action | AA Sequence (Left, N-Terminal) |
|---|---|---|---|
| CRH | 40 | Binds to receptor on corticotrope to release ACTH, β-endorphin, and lipotropin |
|
| GHRH | ~44 | Binds to receptor on somatotrope for GH secretion |
|
| Somatostatin | 14 | Binds to receptor on somatotrope to inhibit release of GH |
|
| GnRH | 10 | Binds to receptor on gonadotrope to release LH and FSH | pyro-EHWSYGLRPG-NH 2 |
| TRH | 3 | Binds to receptor on thyrotrope to release TSH | pyro-EHP-NH 2 |
| PRF (unknown, but TRH, OT, and estrogen can release prolactin) | Binds to receptor on lactotrope to release prolactin | ||
| PIF; probably dopamine; leukemia inhibitory factor also inhibits |
The first AA of a peptide sequence is the N-terminal AA. AA , Amino acid; ACTH , adrenocorticotropic hormone; CRH , corticotropin-releasing hormone; F , factor; FSH , follicle-stimulating hormone; GH , growth hormone; GHRH , growth hormone–releasing hormone; GnRH , gonadotropin-releasing hormone; H , hormone (releasing hormones are known structures); LH , luteinizing hormone; OT , oxytocin; PIF , prolactin release inhibiting factor; PRF , prolactin-releasing factor; TRH , thyrotropin-releasing hormone; TSH , thyroid-stimulating hormone.
In general, the secretion of the releasing hormones is episodic; they enter the closed portal circulation in extremely small amounts that are large enough to activate their receptors (the amount reaches the binding constant of the cognate receptor, or higher), and these activated receptors set off a signaling chain of events (elevated cAMP or phosphatidylinositol, or both) that culminate in the release of the pituitary hormone and usually affect the activation of the gene that encodes the mRNA of the pituitary hormone so that amounts of the pituitary hormone are synthesized for storage in the cell. The pituitary hormones circulate in the blood and bind to their receptors in the tissue cells of their targets generating a response at the tissue level. The combination of all the tissue responses produces the bodily response to the hormone. The signaling system for hormones starting with the hypothalamus is summarized in Fig. 15.2 .
Signaling From Hypothalamus to Posterior Pituitary
OT is released from nerve endings in the posterior pituitary by stimulation of the nipples and in lactating women will aid in release of milk from the breast. There are hypothalamic interneurons (neurons impinging on the cell body of the OTergic neuron ) that electrically stimulate the OTergic neuron to release OT from the posterior pituitary nerve endings (site of storage) by the process of exocytosis (discharge of components stored in vesicles) when the nerve endings are depolarized (alteration of charges on the surface of the nerve ending, usually a loss of outside negative charges). OT is initially released as a large polypeptide that includes the sequence of the OT carrier protein neurophysin I . The polypeptide precursor is broken down by a number of proteases, the final one being peptidylglycine α-amidating monooxygenase releasing the nine amino acid–containing peptide, OT, and the intact neurophysin I ( Fig. 15.3 ).
OT and neurophysin I form a complex for the stabilization of OT in the bloodstream. The complex dissociates before OT binds to its receptor on the surface of the plasma membrane of the target cell. OT also can be released from the hypothalamic OTergic neuron by estrogen. There are extrahypothalamic organs that contain OT; however, the functions of OT in these tissues are not well known. Tissues, besides the brain, that contain OT and/or its receptor are corpus luteum , Leydig cells, retina, placenta, pancreas, adrenal medulla, heart, and thymus.
VP (usually AVP ) is stored in VPergic nerve endings in the posterior pituitary . The release of AVP is stimulated by a fall in blood pressure, a decrease in blood volume, and, in general, any condition where the blood volume is decreased. Because the action of AVP on the kidney is to cause the reabsorption of water into the bloodstream, the initial signals are neutralized by this activity. AVP, but not OT, can be released by nicotine (smoking cigarettes can have this activity). The gene encoding the mRNA for AVP contains responsive elements at its N-terminus: these are osmolar response element , glucocorticoid response element , estrogen response element , and fos/jun response element ( API-RE ). The polypeptide precursor containing VP and neurophysin II (its carrier protein) and another polypeptide ( copeptin ) are hydrolyzed by enzymes, like the case of OT precursor maturation, to release the mature products, VP and neurophysin II. While AVP has a short half-life (c.5–15 minutes) and is somewhat unreliable as a measure of osmolality for that reason, copeptin is much more reliable because of its greater stability. The level of copeptin in blood is a direct indicator of the level of AVP and also mirrors the levels of stress-induced cortisol . Copeptin level appears to be a predictor of the severity of hemorrhagic and septic shock and high levels of copeptin predict an elevated mortality risk for heart failure patients.
AVP and neurophysin II form a complex and remain in complex form for the stability of AVP until AVP binds to its receptor on target cells of the kidney to increase reabsorption of water, ultimately into the bloodstream. The gene for VP-neurophysin II and copeptin and the maturation products are shown in Fig. 15.4 .
The structures of OT and AVP are similar with differences in only two amino acids out of nine (both hormones are nanopeptides) as shown in Fig. 15.5 .
Hormonal Signaling From the Hypothalamus to the Anterior Pituitary
The releasing hormones from the hypothalamus are secreted into the closed portal system contained in the stalk and reach their cognate receptors on the cell membrane of the target cell as outlined in Table 15.1 .
Stimulation for release of releasing hormones in the hypothalamus derives from either aminergic or peptidergic hormones that are released from interneurons that impinge upon the cell bodies of neurons containing the releasing hormones. These earlier signals would generate in response to internal or external signals, and some of the effects elicited by them would be inhibitory as well as stimulatory. Some specific stimuli are known for the secretion of certain releasing hormones. In the case of the secretion of the GHRH and somatostatin ( SS ) of the hypothalamus, cAMP stimulates the release of both hormones. Another stimulant is a calcium ionophore indicating that the calcium messenger system could be involved. Thyrotropic-releasing hormone ( TRH ) released from neurons in the paraventricular nucleus of the hypothalamus is stimulated directly by the hormone, leptin . Leptin increases melanocortin [α-melanocyte-stimulating hormone (α-MSH)] that is required for TRH expression. The melanocortin system activates the TRH promoter on DNA through the phosphorylation of the signal transducer and activator of transcription 3 ( Stat3 ). The Stat response element in the TRH promoter is required for the effects of leptin. Undoubtedly, there are many other signals that cause the release of the releasing hormones into the closed portal system leading to the pituitary.
Releasing hormones bring about the release of the relevant hormones from the anterior pituitary into the general circulation and, in some cases, the resynthesis of the anterior pituitary hormone is activated. The anterior pituitary hormones and their general actions are listed in Table 15.2 .
Table 15.2
Hormones of the Anterior Pituitary.
| Hormone | Number of Amino Acid Residues (MW) | Action |
|---|---|---|
| ACTH | 39 (4540 Da) | Signals adrenal cortex to release/synthesize cortisol (also 2-degree stimulus for aldosterone) |
| GH, somatotropin | 191 (22,124 Da) | Stimulates growth, lipid, and carbohydrate metabolism especially in liver and adipose; releases IGF-1: stimulates bone sulfation |
| FSH | 82 Amino acids in α-subunit; 118 amino acids in β-subunit; (35,500 Da for FSH) | Stimulates growth and maturation of ovarian follicles; with estrogen, stimulates the formation of LH receptors on granulosa cells in late follicular phase; with testosterone, supports spermatogenesis (FSH, LH, TSH all share the same α-subunit: β-subunit differs in each) |
| LH | α-Subunit, 96: β-subunit, 121 amino acids (~28,000 Da for LH) | Stimulates secretion of sex hormones from male and female gonads; in males, LH acts on Leydig cells to stimulate synthesis and secretion of testosterone; in females, LH stimulates theca cells to secrete testosterone that is converted to estrogen in nearby granulosa cells |
| Prolactin (luteotropin, LH) | 199 amino acids (23,000 Da) | Growth/development mammary gland, synthesis of milk, and maintenance of milk secretion; stimulates progesterone secretion; role in immune response; acts on PRL receptor and certain cytokine receptors; suppresses gonadotropins (its secretion inhibited by dopamine) |
| TSH | 211 amino acids 2 subunits (α and β) (28,500 Da for TSH) | Stimulates secretion and synthesis of thyroid hormone (T4 and T3) from thyroid gland (α-subunit identical to that for FSH and LH) |
| MSH |
|
Skin darkening; central nervous system actions |
ACTH , Adrenocorticotropic hormone; FSH , follicle-stimulating hormone; GH , growth hormone; IGF , insulin-like growth factor; LH , luteinizing hormone; MSH , melanocyte-stimulating hormone; MW , molecular weight; PRL , prolactin; TSH , thyroid-stimulating hormone.
ACTH and the MSH s arise from the same protein precursor as shown in Fig. 15.6 .
The pars intermedia –like cells are scattered between the anterior and posterior pituitary in the human, whereas in lower forms the pars intermedia forms a discrete organ. Note that in the pars intermedia –like cells, there is an absence of ACTH since it is broken down into α-MSH and the hormone corticotropin-like intermediate peptide (CLIP). The absence of ACTH coincides with the fact that these cells also do not contain the glucocorticoid receptor that would be needed for negative feedback by cortisol on the production of ACTH (which does occur in the corticotrope of the anterior pituitary). In the negative feedback mechanism the terminal hormone (e.g., cortisol ) feeding back binds to its receptor ( glucocorticoid receptor ) in the cells producing the signal (ACTH or CRH in the hypothalamus ) for the release of the terminal hormone. The receptor in those cells sets off a signal pathway leading to an inhibition of further release of the hormone normally secreted by that cell. CLIP appears to act on the endocrine pancreas and causes the release of insulin from the β-cell. In the exocrine pancreas , CLIP acts like the hormone secretin and stimulates enzyme release (this has been shown for the secretion of the enzyme, amylase ).
Hormones are split out of the precursor peptide by proteases that are specific for the Arg–Lys or Lys–Arg linkages, and the location of these sites is shown at the top of Fig. 15.6 . Some hormones are generated primarily in the anterior pituitary cells and some others arise in the pars intermedia –like cells. The release of γ-MSH, ACTH, and β-lipotropin (β-LPH) is mainly from anterior pituitary cells. In the pars intermedia –like cells, ACTH is broken down further to release α-MSH and CLIP. β-LPH is broken down to γ-LPH and β-endorphin (β-END). The latter two serve as precursors for β-MSH and Met-enkephalin .
The anterior pituitary (also, adenohypophysis) is composed of five cell types. The somatotrophs ( somatotropes ) represent 50% of the cell population and produce GH (its release is signaled by the hypothalamic GHRH ). The lactotrophs ( lactotropes ) produce PRL and represent 20% of the anterior pituitary cells. Another 20% of the cell population is represented by the corticotrophs ( corticotropes ) that synthesize the ACTH (corticotropin, ACTH ). Thyrotropic hormone ( thyroid-stimulating hormone , thyrotropin , TSH ) is produced by the thyrotrophs ( thyrotropes ) that occupy 5% of the cells in the anterior pituitary. The gonadotrophs ( gonadotropes ) occupy another 5% of the cells and produce both FSH and LH stored in separate compartments in the same cell. The release of both FSH and LH is signaled by the GnRH . The “troph” ending on the name of the anterior pituitary cell type indicates that its secretory product induces a growth response in the target cell, whereas the “trope” ending on the name of the cell type indicates that its secretory product induces changes in the target cell; the two terms are often used interchangeably. A hormone like ACTH causes the synthesis and release of cortisol (tropic effect) from the adrenal cortex cell target and is also a growth factor for the cells producing cortisol (trophic effect). In the absence of ACTH the adrenal cortical cells producing cortisol will die.
Virtually, all polypeptide hormones and neurotransmitters, including those derived from amino acids (e.g., norepinephrine), are ligands for receptors located in the cell membrane or on the surface of the target cell, whereas steroid hormones pass through the cell membrane in both directions but are tethered within the cell by binding to cytosolic receptors or receptors within the cell nucleus (a very small portion of some steroid hormone receptors are located in the cell membrane and bring about rapid, nontranscriptional effects, such as stimulating ion transport); however, these receptors have been shown to be different from the classical cytosolic receptors. The thyroid hormones , thyroxine ( T4 ) and triiodothyronine ( T3 ), bind to the thyroid hormone receptor that is localized within the nucleus, forming an exception since it is not located in the cell membrane and is grouped as a member of the steroid receptor gene family . In Fig. 15.7 a generalized scheme is shown of the signal pathways from the hypothalamic hormones through the anterior pituitary hormones to the end target cells and the actions produced by the terminal hormones.
Models of Hormone Action of Anterior Pituitary Hormones
Adrenocorticotropic Hormone
The ACTH is released from the anterior pituitary corticotrope by the hypothalamic-releasing hormone , CRH (the corticotropic-releasing hormone ). ACTH activates its receptor on the cell membrane of the zona fasciculata cell of the adrenal cortex (the intermediate layer of the cortex) and the signaling pathway that follows generates the synthesis of cortisol and its release into the bloodstream (through the adrenal medulla) as shown in Fig. 15.8 .
α-Melanocyte-Stimulating Hormone; Melanotropin, Intermedin
There are three MSH molecules: α-MSH (13 amino acids), β-MSH (18 amino acids), and γ-MSH (11 amino acids). α-MSH is secreted from cells located between the anterior and posterior pituitary lobes. Whereas lower forms have discrete structures resembling an intermediary lobe , the human has only scattered cells in the same region, having the same properties as if they were located in a discrete lobe. The precursor polypeptide generating these MSH molecules as well as other molecules, including ACTH , β- and γ-LPHs, CLIP and β-END, is proopiomelanocortin ( POMC ). Whereas ACTH remains intact in the corticotropic cell of the anterior pituitary, in the intermediary cells, ACTH is degraded completely to α-MSH and CLIP; consequently, in these cells, ACTH acts as an intermediate.
There are five melanocortin receptors ( MCRs ). MC1R binds α-MSH primarily but can also bind ACTH, β-MSH, and γ-MSH with much lower affinity. The function of MC1R is in the regulation of melanin production. MC2R binds ACTH almost exclusively for the production of cortisol (and to a small extent aldosterone) in cells (primarily zona fasciculata cells) of the adrenal cortex. MC3R binds γ-MSH with a lower affinity toward α-MSH and β-MSH for the action upon energy homeostasis and energy partitioning. MC4 receptor (MC4R) primarily binds β-MSH, to a slightly lesser extent α-MSH, and has a reduced affinity for γ-MSH. MC5R prefers to bind α-MSH, to a lesser extent ACTH, β-MSH, and γ-MSH for the production of sebum (oily secretion of sebaceous glands). The generation of important peptides from POMC in the pituitary and the overall roles of the five MCRs with their binding preferences are summarized in Fig. 15.9 .
The actions of MSH in the production of melanin pigment and in the neural regulation of feeding and antiinflammation are of special importance. With regard to the action of α-MSH, in the production of melanin, Fig. 15.10 shows that α-MSH binds to the MC1R (receptor) on the cell membrane of the melanocyte to increase the production of the skin-darkening pigment, melanin, in its various forms.
In the melanocytes, α-MSH regulates the synthesis of melanin forms in the pigment granules. The other forms of MSH (β and γ) can also stimulate melanin synthesis but to a much lesser extent than the α-form as witnessed by the binding preferences for MC1R shown in Fig. 15.9 . Melanocytes are located in the basal layer of the skin epidermis where they comprise 5%–10% of the cells in this layer. Melanosomes (the granules in the melanocyte containing melanin) are transferred from melanocytes to neighboring keratinocyte s ( Fig. 15.11 ). Keratinocytes are located in the surface of the skin epidermis and constitute 95% of the cells in this layer. Keratinocytes, consequently, can secrete α-MSH.
Melanin absorbs all of the UV-B light (315–280 nm) to prevent the damaging effects of those rays on DNA. Melanocytes are also found in the uvea (middle layer) of the eye, in the inner ear and elsewhere and melanin provides the coloration of skin, eyes, and hair. In the case of blue eyes , it is thought that the uvea contains less melanin, and the light passes to deeper layers of the eye to be scattered by resident proteins. The scattered light reflects back through the iris and appears blue to the onlooker. It is possible that in the case of green or hazel eye colors, there is slightly more melanin than in blue eyes to account for the difference in color. Recent research ( ) shows that melanin is a porphyrin-like structure in melanin pigments.
In Cushing’s disease , excess ACTH is produced providing more precursor for α-MSH. Accordingly, there is usually a hyperpigmentation of the skin. In Addison’s disease where insufficient cortisol is produced by the adrenal cortex, there is a reduced negative feedback on the production of ACTH providing more α-MSH and a darkening of the skin even in areas not exposed to sunlight.
α-MSH has potent antiinflammatory effects. These are mediated by antagonizing the effects of proinflammatory cytokines as well as by decreasing the concentrations of key inflammatory mediators. The antiinflammatory actions of α-MSH operate through the MC4R to produce cAMP and the subsequent activation of protein kinase A ( PKA ). PKA phosphorylates CREB ( cAMP-responsive element-binding protein ) and the activated CREB binds to cAMP-responsive element sequences in target genes. Signals for inflammation lead to transfer of NF- κB to the nucleus and subsequent production of inflammatory cytokines. The action of PKA (initiated by activated MC4R) prevents the breakdown of the inhibitor of NF-κB nuclear transport and reduces the production of proinflammatory cytokines, such as iNOS ( induced nitric oxide synthase ) and Cox-2 ( cyclooxygenase-2 ). Both of these enzymes lead to the production of inflammatory cytokines (although the role of iNOS in inflammation is incompletely understood). Cox-2 increases the production of inflammatory prostaglandins .
The neural effects of α-MSH are mediated by the activation of MC4R. Normally, NPY ( neuropeptide Y ) stimulates feeding, whereas α-MSH inhibits NPY-stimulated feeding by activating the MC4R in the regulatory hypothalamic neurons. α-MSH, operating through this receptor, inhibits the tonic release of NPY. Theoretically, the balance between NPY and α-MSH regulates appetite and feeding behavior.
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