In addition to adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH) also stimulates the secretion of β-endorphin and other proopiomelanocortin (POMC: see section IV.D following) derived peptides from the anterior pituitary. In other areas of the brain CRH is an important mediator of responses to stress. It is also an important placental hormone involved in the events of parturition. The primary structure of CRH, which is located in the carboxyl terminus of the 196-amino acid pre-prohormone, is shown in Figure1. Pre-proCRH is encoded by the second of the two exons in its gene. Processing involves the prohormone convertase catalyzed cleavage of CRH from the prohormone precursor and the amidation of the carboxy terminal; this amide group is required for biological activity.

Fig1. Hypothalamic peptides that control anterior pituitary hormone secretion. The amino acid sequences of some important hypothalamic regulatory peptides are indicated schematically, reading left to right, N- terminal to C-terminal. TRH and GnRH, the smallest of the peptides, have modifications on both ends, with a pyroglutamyl moiety (red hexagon; see Figure 3-8 for structure) and amidation of the C-terminal carboxyl group (yellow diamond). CRH and GHRH have only the N-terminal modification, whereas somatostatin is not modified at either end. The sequence of somatostatin-28 is shown with both lightly and darkly shaded circles. The darker carboxyl terminal 14 amino acids are those of somatostatin-14.

The cell bodies of the neurons that synthesize and secrete CRH into the hypothalamic-pituitary portal system are located in the paraventricular nucleus of the hypothalamus. Neuronal input to these neurons is from the limbic system (amygdala and hippocampus) and brainstem regions governing autonomic functions. CRH is found in other areas of the central nervous system including the cerebral cortex, limbic system, cerebellum, brain stem, and spinal cord.

In the CRH synthesizing neurons functioning as part of the hypothalamic-pituitary-adrenal axis, glucocorticoid receptor (GR) activation by the steroid hormone can repress transcription from the crh gene as part of negative feedback in the mouse; the precise mechanism by which this occurs has not yet been elucidated. On the other hand, stress-related noradrenergic and glutamatergic excitatory signals can activate the gene, in part via activation of the transcription factor CREB (cyclic AMP response element binding protein). A second protein, TORC (transducer of regulated CREB activity), plays a vital role in cyclic AMP mediated regulation of CRH expression in these neurons. The regulation of CRH gene expression is localization-specific; for example, in other areas of the brain and in the placenta glucocorticoids stimulate, rather than inhibit, CRH gene transcription.

There are two forms of the CRH receptor: CRH R1, encoded on chromosome 17 in humans, and CRH-R2 on chromosome 7. Both belong to the class II G-protein coupled receptor superfamily and contain seven membrane-spanning regions. The genes for each of the two receptors consist of more than a dozen exons and alternative splicing of these leads to several sub-forms of the receptor with various activities. The two CRH receptors share about 70% amino acid identity, with most of the divergence coming at the N-terminal region of the molecules. CRH-R1 mediates the effects of CRH in the anterior pituitary corticotrophs but is widely distributed elsewhere in the brain. It also occurs in peripheral tissues such as those of the reproductive tract, the adrenal gland, adipose tissue, cardiac muscle, and some cells of the immune system. CRH-R2 has very specific locales in the brain and can also be found in peripheral tissues.

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مواضيع ذات صلة

Regulation and Biological Actions of Growth Hormone and Prolactin

Hypothalamic Control of Growth Hormone Secretion

The Physiology of Vasopressin

Gonadotropin-Releasing Hormone

Thyrotropin-Releasing Hormone

Biosynthesis of Adrenal Cortex Mineralocorticoids, Glucocorticoids, and Some Androgens

Mechanisms of hormone action: Cell Signaling by Membrane Receptors

Biosynthesis of Peptide and Protein Hormones

Hormones and Their Communication Systems

Stepwise development of tissue- specific insulin resistance

Insulin resistance in adipose tissue Adipose tissue

Insulin resistance in the liver