Potential of a quantal response as a mechanism for oscillatory behavior: implications for our concepts of hormonal...

This article describes the potential of a quantal (i.e., all-or-none) response as a model for understanding the interactions between endocrine, paracrine and autocrine hormones. We review the general features of continuous and discontinuous (i.e., oscillating) quantal models including the role of a threshold. In addition, we also describe a few of the many different biochemical mechanisms which may give rise to quantal behavior. One of the more attractive schemes involves the coordinate regulation of opposing biochemical pathways resulting from phosphorylation of hormone receptors and/or rate-limiting enzymes. At least one hormone receptor (i.e., that for insulin) and many rate-limiting enzymes which control the flow of metabolites through a variety of metabolic pathways can be phosphorylated at multiple sites by one or more protein kinases. Phosphorylation may enhance or inhibit the activities of these proteins depending on which sites are modified. Furthermore, since phosphorylation of some sites on a protein may enhance the ability of phosphoprotein phosphatases to dephosphorylate other sites responsible for biological activity of the protein, phosphorylation also has the potential to produce a discontinuous quantal response. Quantal response mechanisms may alter our notions of endocrine regulation. When a quantal response mechanism is applied to a simple negative feedback model similar to that which was originally postulated to explain the interactions between gonadotropin and steroid hormonal levels, the model can account for the oscillations in hormone levels even when the input is constant. Conversely, when a graded mechanism is applied to the same negative feedback model, the model will almost certainly result in constant hormone levels. Further, the model illustrates that small changes in rate constants and thresholds of response, amplification of hormonal signals, and degradation of intermediate regulators can produce large shifts in the output of the system. These may account for the variability in hormonal levels observed in some endocrine systems. Finally, the high sensitivity of the quantal response mechanism accounts for the data which suggest that gonadotropins may play permissive rather than causal roles in regulation of gonadal function. Since increasing evidence suggests that all cells of a given type may not be equal in terms of hormonal responsiveness, measurements of response in single cells over short time periods will be needed before the role of a quantal response can be determined and endocrine regulation will be fully understood.