James P. Harwood

Hormonal regulation of peptide receptors and target cell responses

Regulation of plasma membrane receptors for peptide hormones by the prevailing ligand concentration often causes altered target cell function. Receptor number is determined by hormone-induced changes in membrane conformation, irreversible ligand binding, and processing of ligand–receptor complexes during hormone action.

Regulation of peptide hormone receptors and gonadal steroidogenesis.

Publisher Summary This chapter discusses regulation of peptide hormone receptors and gonadal steroidogenesis. The control of gonadal function by gonadotropins and prolactin is expressed through activation of plasma-membrane effector systems following hormone binding to specific, high-affinity receptors on the target-cell surface. Hormonal stimulation of characteristic gonadal responses by gonadotropins is predominately mediated by the adenylate cyclase protein kinase pathway, whereas the nature and mechanism of prolactin actions are less defined. Peptide hormones comprise one of the major groups of chemical signals by which intercellular communications operate within the organism. The low concentrations at which hormones circulate are commensurate with the high affinities of their cell-surface receptor sites, and the marked specificities of such receptors permit recognition of the circulating hormone amid a vast excess of other protein molecules. These well-defined binding properties of peptide receptors are similar to those of antigen-antibody reactions. In B lymphocytes, the immunoglobulin molecule serves as a surface receptor comparable to the peptide hormone receptor. The ability of peptide hormones to regulate the concentrations of their specific receptor sites in endocrine target cells is demonstrated in numerous tissues.

Receptor-mediated actions of corticotropin-releasing factor in pituitary gland and nervous system.

High-affinity corticotropin-releasing factor (CRF) receptors which mediate the actions of the hypothalamic peptide on adrenocorticotropic hormone (ACTH) release have been identified in the rat anterior pituitary gland. Occupancy of the pituitary receptor by CRF agonists stimulates ACTH release via activation of adenylate cyclase and cyclic adenosine monophosphate dependent protein kinase. In the regulation of ACTH secretion, the effects of CRF on the corticotroph are integrated with the stimulatory actions of cyclic adenosine monophosphate-independent stimuli such as angiotensin II, vasopressin and norepinephrine, and the inhibitory effects of glucocorticoids and somatostatin. In contrast to the major importance of the inhibitory effect of glucocorticoid feedback on ACTH secretion, somatostatin has relatively little effect on CRF-stimulated ACTH release in the normal rat corticotroph. Following adrenalectomy, the progressive elevation of plasma ACTH levels is accompanied by a concomitant decrease in pituitary CRF receptors. The postadrenalectomy loss of CRF receptors, which is prevented by dexamethasone treatment, is caused by a combination of occupancy and processing of the pituitary sites during increased secretion of the hypothalamic peptide. Recently, specific receptors for CRF have been localized in the rat and monkey brain and adrenal medulla, where they are also coupled to adenylate cyclase. Brain CRF receptors are most abundant in the cerebral and cerebellar cortices and in structures related to the limbic system and control of the autonomic nervous system. The actions of CRF on the central and peripheral nervous systems, as well as on the pituitary gland, emphasize the role of CRF as a key hormone in the integrated response to stress.

Luteal Desensitization: Hormonal Regulation of LH Receptors, Adenylate Cyclase and Steroidogenic Responses in the Luteal Cell

Regulation of peptide hormone receptors and target cell responses by increased concentrations of the homologous hormone has been demonstrated in a number of endocrine-dependent tissues (1–6). This process, described variously as desensitization, tachyphylaxis, refractoriness, tolerance, and down-regulation, is particularly marked in the testis and ovary following exposure to elevated gonadotropin levels (5–12). The finding that insulin (1) and growth hormone (2) are able to regulate their own receptor sites in target cells was followed by the demonstration of an inverse relationship between ligand concentration and receptor number for several other hormones, including catecholamines (3), thyrotropin releasing hormone (4) and gonadotropins (5–12). Although such negative regulation of receptor sites is now recognized to be a wide-spread property of peptide hormones, it should be noted that certain hormones, such as prolactin (13) and angiotensin (14) exert positive regulation upon their receptor sites, with an increase in binding capacity of the target cells in response to elevated hormone concentration.

Corticotropin Releasing Factor Receptors: Characterization and Actions in the Anterior Pituitary Gland

Corticotropin releasing factor (CRF), which was isolated from hypothalamic extracts and sequenced in 1981, has been shown to participate in visceral and behavioral responses to stress, as well as the control of ACTH secretion (1,2). The initial event in the action of CRF in the pituitary gland is its binding to specific plasma membrane receptors, which trigger the formation of intracellular messengers responsible for the activation of ACTH release. Such receptors were first identified in rat pituitary membranes by binding studies with radioiodinated CRF (3), and were subsequently analyzed by radioassays in membranes (4) and by autoradiographic (5–8) and cytochemical techniques using biotinylated or fluorescein-conjugated CRF analogues (9,10). The use of autoradiography permitted the identification and characterization of CRF receptors in the central and peripheral nervous systems, and has greatly aided our understanding of the physiological actions of CRF in these tissues. The most common ligand used for CRF receptor studies is the radioiodinated ovine CRF derivative, Tyr-oCRF; similar receptor properties have been described using radioiodinated [NLeu21, Tyr32]oCRF (5). Analogues of rat/human CRF have given tracers with reduced biological action and lower binding activity due to peptide damage during the iodination procedure. Since ovine and human CRF bind to the CRF receptor in different species with equal affinities, oCRF can be used for studies in both rat and primates.