Chemistry

The releasing hormones that have been sequenced will be referred to as hormones, whereas the others, whose activity is measurable but whose primary structure is unknown, will be referred to as "factors." There are two kinds of releasing hormone systems in the hypothalamus: one in which a single releasing hormone appears to positively control the secretion of a given anterior pituitary hormone, and the other in which a pair of releasing hormones, one acting positively and one acting negatively, modulates the secretion of a specific anterior pituitary hormone (Table 31). As time goes on, negative controlling factors are discovered, so that in fact, all anterior pituitary hormones may be controlled ultimately in their secretion by a primary set of positive and negative releasing hormones.

In the single-controlling set are thyrotropin-releas-ing hormone (TRH), gonadotropin-releasing hormone (GnRH), and corticotropin-releasing hormone (CRH). All of these act positively on the release of thyroid-stimulating hormone from thyrotropic cells of the anterior pituitary (TRH), prolactin from lactotrophic cells of the anterior pituitary (PRL), luteinizing hormone (LH) from luteotrophic cells of the anterior pituitary (GnRH), follicle-stimulating hormone (FSH) from folli-culotrophic cells of the anterior pituitary (GnRH), and finally adrenocorticotropin from corticotrophic cells of the anterior pituitary (CRH). Some evidence suggests that LH and FSH can be secreted from the same cell, that is, that luteotrophs and folliculotrophs may be one

FIGURE 3-5 Drawing of a neuron (center) that is synthesizing and secreting a releasing hormone and its regulation by aminergic neurons (interneurons), which in this case secrete serotonin, dopamine, and norepinephrine. The regulatory interneurons synapse with the cell body in this illustration. The catecholamines are usually synthesized in the nerve ending. The releasing hormones and precursors are synthesized in the cell body and transported down the axon to the nerve terminal where the signal is awaited for release. Afterward, the releasing hormone enters the closed portal circulation through capillary fenestrations in the primary plexus. After transport down the portal vessel, the hormone empties from the secondary plexus into the anterior pituitary. This figure was redrawn and modified from Frohman, L. A. (1980). Neurotransmitters as regulators of endocrine function. In "Neuroendocrinology" (D. T. Krieger and J. C. Hughes, eds.), pp. 44-58. Sinauer Associates, Sunderland, Massachusetts.

FIGURE 3-5 Drawing of a neuron (center) that is synthesizing and secreting a releasing hormone and its regulation by aminergic neurons (interneurons), which in this case secrete serotonin, dopamine, and norepinephrine. The regulatory interneurons synapse with the cell body in this illustration. The catecholamines are usually synthesized in the nerve ending. The releasing hormones and precursors are synthesized in the cell body and transported down the axon to the nerve terminal where the signal is awaited for release. Afterward, the releasing hormone enters the closed portal circulation through capillary fenestrations in the primary plexus. After transport down the portal vessel, the hormone empties from the secondary plexus into the anterior pituitary. This figure was redrawn and modified from Frohman, L. A. (1980). Neurotransmitters as regulators of endocrine function. In "Neuroendocrinology" (D. T. Krieger and J. C. Hughes, eds.), pp. 44-58. Sinauer Associates, Sunderland, Massachusetts.

and the same or that both types of cells may exist. In the set of dual-controlling releasing hormones, there are growth hormone-releasing hormone (GRH) and growth hormone release-inhibiting hormone (GIH or somatostatin) and prolactin-releasing factor (PRF) and prolactin release-inhibiting factor (PIF). The structures of the releasing hormones with known sequences are shown in Figure 3-8. Ultimately, it may be discovered

FIGURE 3-6 Drawing of a neuron showing the cell body with a number of branching dendrites (Den). The axon (Ax) extends from the pole opposite that giving rise to dendrites. It has a large, round nucleus (N) with a nucleolus (NI). The rough endoplasmic reticulum is organized into an aggregation of cisternae studded with ribosomes (R), known as Nissl substance (NiS). Smooth-surfaced endoplasmic reticulum (SER) is extensive and tubular. The Golgi apparatus (G) is a short stack of flattened cisternae with small vesicles (V); dense core vesicles (DV) may contain catecholamines. Lysosomes (Ly) are numerous. Intermediate stages between lysosomes and lipofuscin granules (LPG) are found. Microtubules (Mt) course from the perikaryon into the axon (Ax). Neurofilaments (Nf) and smooth endoplasmic reticulum run into the axon. Other abbreviations: Sy, synapse; SV, synaptic vesicle; SA, spine apparatus, SsW, subsynaptic web; SsC, subsurface cisternae. Reproduced from Lentz, T. L. (1971). "Cell Fine Structure." Saunders, Philadelphia, Pennsylvania.

FIGURE 3-6 Drawing of a neuron showing the cell body with a number of branching dendrites (Den). The axon (Ax) extends from the pole opposite that giving rise to dendrites. It has a large, round nucleus (N) with a nucleolus (NI). The rough endoplasmic reticulum is organized into an aggregation of cisternae studded with ribosomes (R), known as Nissl substance (NiS). Smooth-surfaced endoplasmic reticulum (SER) is extensive and tubular. The Golgi apparatus (G) is a short stack of flattened cisternae with small vesicles (V); dense core vesicles (DV) may contain catecholamines. Lysosomes (Ly) are numerous. Intermediate stages between lysosomes and lipofuscin granules (LPG) are found. Microtubules (Mt) course from the perikaryon into the axon (Ax). Neurofilaments (Nf) and smooth endoplasmic reticulum run into the axon. Other abbreviations: Sy, synapse; SV, synaptic vesicle; SA, spine apparatus, SsW, subsynaptic web; SsC, subsurface cisternae. Reproduced from Lentz, T. L. (1971). "Cell Fine Structure." Saunders, Philadelphia, Pennsylvania.

that all anterior pituitary hormones are governed in their release by both positive and negative releasing factors.

GRH is a polypeptide. /^-Endorphin is active in causing the release of growth hormone and PRL and in inhibiting the release of gonadotropins and TSH. [i-Endorphin arises from the proopiomelanocortin precursor in corticotrophic cells of the anterior pituitary. It is a cleavage product of /3-lipotropin, which is directly translated to proopiomelanocortin. It is possible that ^-endorphin could stimulate GH release indirectly by increasing the release of GRH or inhibiting the release of somatostatin. A peptide and its partial degradation products have been discovered by the R. Guillemin group in human pancreatic carcinoma. This 44-amino acid peptide possesses growth hormone-releasing activity and appears to be human GRH. Its structure is shown in Figure 3-8.

PIF is closely related to dopamine, and this neurotransmitter may be identical to PIF. However, there is some evidence that not all PIF activity in the hypothalamus can be attributed to dopamine. Again, however, dopamine could be acting to modify (stimulate) the secretion of another unique PIF. The structure of dopa-

CRH, the corticotrophic releasing hormone, is a polypeptide, and there is an auxiliary hormone to CRH, which is vasopressin. Vasopressin is synthesized in the hypothalamus and can release ACTH when injected directly into the brain, but depends upon CRH; it stimulates the activity of CRH. The structure of vasopressin is given in Chapter 4.

a-MSH normally derives from the intermediate pituitary cells under the control of dopamine, not CRH. There may be certain disease conditions leading to abnormally produced a-MSH, perhaps from the unex

RECEIVING CELL ACETYLCHOLINE OR OTHER

RECEIVING CELL ACETYLCHOLINE OR OTHER

FIGURE 3-7 Diagram of a neuron (in this case, cholinergic) whose secretion is regulated by an enkephalinergic interneuron interacting at the nerve ending to modify secretion as mediated by opiate receptors. Reproduced from Agnew, D. (1970). City of Hope Quart. 8, 6-10.

pected breakdown of ACTH derived from the corticotropin Proteolytic cleavage products of oxytocin and vasopressin have been shown to result from the action of proteolytic enzymes present in brain synaptic membrane preparations. Some of these products may be active in the release of various pituitary hormones. It is presumed that some or all of these products will also have neurotransmitter or other direct functions in the CNS. In contrast to known brain aminopeptidases, synaptic (nerve ending) membrane-associated enzymes can cleave oxytocin or vasopressin without a prior requirement for reduction of the disulfide bridge. Releasing hormones (excluding GRH and CRH, which need more information) are not synthesized from mRNAs directly on polysomes, but rather evolve through the cleavage of proproteins of considerably larger size. This is also true of some anterior pituitary hormones, such as ACTH and /3-lipotropin, and their potentially active breakdown products that derive from a single protein precursor, proopiomelanocortin. In humans, a-MSH derives from the intermediate pituitary cells from proopiomelanocortin under dopamine

TABLE 3-1 Well-Characterized Hypothalamic Releasing Hormones-Factors"

Hypothalamic positive-acting single hormone Thyrotropin-releasing hormone (TRH, protirelin) Gonadotropin-releasing hormone (GnRH, gonadorelin, buserelin, goserelin, leuprolide, nafarelin, triptorelin) Corticotropin-releasing hormone (CRH, corticoliberin)

Dual-acting releasing hormone

Growth hormone-releasing hormone (somatocrinin, GRH, somatoliberin)

Growth hormone release-inhibiting hormone (somatostatin,

GIH, SRIF) Prolactin-releasing factor (PRF protirelin)' Prolactin release-inhibiting factor (PIF)fc

Inhibits release of anterior Releases anterior pituitary hormone(s) pituitary hormone(s)

TSH, PRL

ACTH, ß-lipotropin, /3-endorphin

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