GHRH is synthesized in the hypothalamus as a 107/108 amino acid precursor (prepro-GHRH) (the 108 isoform contain an extra serine in the carboxy-terminal region), which is later processed to give two peptides [GHRH(1-44)-NH2 and GHRH(1-40)-0H] with similar functions and potency in stimulating GH release.21 Only the first 29 residues are required to exhibit full biological activity.22 GHRH has a plasma half-life of 7-50 min23-25 and it is degraded to inactive forms by dipeptidyl-peptidase type IV and trypsin-like endopeptidases.24,26 Internalization into target cells is another mechanism of GHRH inactivation that has been demonstrated in vitro.21,27
GHRH stimulates somatotroph cell growth28 and GH release.29 These actions are mediated by high affinity, low-capacity receptors.22,30,31 GHRHR is widely expressed in the anterior pituitary gland and partial occupancy causes maximal GH response (only 10-20% of the receptors need to be occupied for maximal GH release).32 GHRHR mRNA has also been identified in the renal medulla33 and in other tissues, such as testes, placenta, and gastrointestinal tract, where it may play a role in paracrine and/or autocrine control.34,35 GHRHR has also been detected in the hypothalamus,36 where GHRH probably functions as a neurotransmitter.34 Splice variants (SVs) of GHRHR have been found in several normal and neoplastic tissues.37
GHRHR expression changes during fetal development and throughout the life. In rat pituitary, GHRHR first appears on embryonic day 19 (E19)38-40 and reaches a peak during E20 with no subsequent increase.41 Receptor expression declines after birth and surges again during puberty. A final decrease in GHRHR expression is seen with aging.42,43
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