Interpretation of dose-response curves for luteinizing hormone release by gonadotropin-releasing hormone, related peptides, and leukotriene C4 according to a hormone/receptor/effector model.

Abstract

The dose-response curves for pituitary luteinizing hormone (Li) release in response to gonadotropinreleasing hormone and its agonists are unusually broad. It appears, however, that these ligands bind to a single class of receptors. It is shown that these dose-response data can be explained by either of two models in which ligand-receptor complexes stimulate LH secretion (i) by interacting with either of two different effector systems or (il) by interacting with a single effector system but forming monomeric and dimeric active effector complexes. A combination of these two basic models can account for the very broad, biphasic dose-response curve reported for LH release in response to leukotriene C4.Gonadotropin-releasing hormone (GnRH: <Glu1-His2-Trp3- [D-Ser(Bu')6IPro9NEt-GnRH}, whereas release in response to the Ca2+ ionophore A23187 or to acyl2Gro span <2 orders of magnitude (2-4).Leukotriene C4 (LTC4) has recently also been shown to stimulate LH release by anterior pituitary cells in primary culture (5). LH secretion is significantly increased with 1 fM LTC4, reaches a maximum at about 1 pM, and then decreases to near-basal levels as LTC4 concentration increases to 0.01MiM-a span of 7 orders of magnitude. Clearly, the doseresponse curves for GnRH, GnRH-A, and LTC4 extend over unusually wide concentration ranges and are of notable complexity.Studies using antibodies to mimic the biological activities of a variety of hormones (e.g., insulin, epidermal growth factor, prolactin, and GnRH) suggest that receptor dimerization may be involved in signal transduction in these systems (ref. 6 and references therein). For example, the GnRHconjugated with a divalent antibody, behaves as a partial agonist (7). LH release initially increases to 66% of the maximum level obtained with GnRH, but then, with increasing concentration of antibody conjugate, declines to basal levels. A good fit to this 5 order of magnitude broad dose-response curve is obtained with a model in which the bivalent conjugate binds to a pair of receptors forming a complex that in turn interacts with and activates an effector (e.g., a Ca2l channel), inducing the cellular response (8).On the other hand, evidence is also accumulating that some hormone-receptor systems may involve two effectors (9). For example, guinea pig ventricular myocytes (10) and rat vascular smooth muscle cells (11) Fig. 1 presents the model that we have used to fit the dose-response curves for GnRH, the superagonist GnRH-A, and LTC4. The ligand, H, interacts with the receptor, R, to form HER, which in turn cin interact with effectors E1 and E2to form the ternary effector complexes H R E1 and H*RTE2.HER may, in addition, interact with these ternary complexes to form the dimerized effector complexes H R'El RH and H-R-E2-R-H. These four effector complexes induce the cellular response (e.g., LH release) at rates that are assumed to Abbreviations: acyl2Gro, diacylglycerol(s); GnRH, gonadotropinreleasing hormone; LH, luteinizing hormone; LTC4, leukotriene C4; GnRH-A, [D-Ser(Bu96]P...

Arachidonate 12-lipoxygenase in porcine anterior pituitary cells: its localization and possible function in gonadotrophs

“…However, 12-HPETE was not tested by these investi¬ gators. Several reports have described that LH release from rat pituitary cells was stimulated by 5-lipoxygenase products: 5-HPETE (Kiesel et al 1987a) and 5-HETE (Naor et al 1983, Kiesel et al 1986, Kiesel & Catt 1987, Miyake et al 1988) at µ concentrations and leukotriene A4, B4, C4 and E4 (Hulting et al 1985, Leiser et al 1986, Kiesel et al 1987a, Miyake et al 1988, Kiesel et al 1991, Dan-Cohen et al 1992) at pM concentrations.…”

A Computer Simulation Model for Automated Quantification of Luteinizing Hormone Secretion

“…Therefore R 0 = 0.01 nM is chosen as standard total receptor concentration. Although, the G proteins per gonadotrope concentration is not known but, it is ~10-fold or more as compared to the number of receptors [20] , It is also chosen that total concentration of G protein to be GQ 0 = 0.1 nM.…”

“…The total receptor concentration R 0 , or the number of GnRHRs per gonadotrope can be taken = 0.01 nM [17,22] and number of G proteins per granadotrope to be GQ = 0.1 nM [20] . The initial value of other variables in equations 1 and 2 such as HR, HRRH, E and IP 3 have the value 0 and R = R 0 .…”

A homotropic two-state model and auto-antagonism

“…This latter type of allosteric behavior is characterized as co-operative, and as such the term "co-operative" is used here in its strict sense only related to auto-modulation [5,8]. Dose-response relations with bell-shapes and terraces have been observed in single ligand applications both for enzymes [9,10], channel-, pump-, and co-transporters [11-14], carriers [15], tyrosine kinase receptors [16,17], and G protein-coupled receptors, GPCRs, for neurotransmitters, hormones, and chemokines [18-25]. …”