A model for intracellular calcium signaling and the coordinate regulation of hormone biosynthesis, receptors and secretion.
A two-state model for the stimulus-induced nongraded response of a single cell is formulated. Individual metestrus gonadotropes stimulated with LHRH operate as a simple switch: either on or off. At a given concentration of stimulus some gonadotropes switch on, while others do not switch on, secretion. The probability of a gonadotrope being in the secretory state is enhanced with each increment of LHRH concentration. Individual gonadotropes in a secretory state are envisioned to decrease their number of LHRH receptors and to switch off LH biosynthesis. On the other hand, individual gonadotropes that are not in a secretory state are thought to increase their number of LHRH receptors and to switch on LH biosynthesis. The group of individuals in the population that have thresholds falling in the range of a given stimulus initiate secretion. And, the group of individuals in the population that have thresholds that fall above the range of a given stimulus do not initiate secretion. More remarkable is evidence that the cells that are protected from hormone secretion nevertheless respond with a set of intracellular signals and this provides a new perspective of how they switch on hormone biosynthesis and up-regulate the LHRH receptors. These changes are envisioned to reduce the threshold of an individual cell and accordingly to enhance the probability that the cell responds in the secretory state with the next stimulus. This scheme would appear to lead to automatic cycles of secretion and biosynthesis since an individual cell can occupy only one of two states at any time and occupancy of either state promotes change to the other. This may provide a solution to the problem of how an endocrine gland might reconcile differences in the time-course of hormone secretion which occurs rapidly and hormone biosynthesis that requires a longer period of time. Parenthetically, the model may also be adapted to the case where the vast majority of individuals in the population are generally subthreshold in relation to the physiological stimulus: such an adaption leads to interesting ways of viewing the mammalian reproductive cycle and the regulation of the preovulatory LH surge. A two-state model of the internal Ca2+ store is outlined here to stimulate thought on how the intracellular signals of each binary state may switch a variety of cellular responses either on or off. The model provides a new perspective on the coordinate regulation of hormone biosynthesis, receptors, and secretion that may be useful in the final reconciliation of population studies with insights about individual cells.
Leong
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DA
Department of Medicine, University of Virginia, Charlottesville.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002451:Cell Compartmentation / Q000187:drug effects; D002468:Cell Physiological Phenomena; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology / Q000502:physiology*; D007986:Luteinizing Hormone / Q000096:biosynthesis*; D008954:Models, Biological; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011966:Receptors, LHRH / Q000187:drug effects / Q000502:physiology*; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
D015220:Calcium Channels; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D002118:Calcium