Synarchic regulation and sensitivity modulation in hormone action.

The present discussion has been concerned with an analysis of experimental data gathered largely in the past decade concerning the relationship of intracellular calcium ion to cAMP. From this analysis, the hypothesis developed is that Ca2+ and cAMP serve as interrelated second messengers when differentiated cells are called upon to perform their particular work function (contraction or secretion, etc.) by extracellular messengers (peptide or amine hormones, neurotransmitters) acting via specific cell surface receptors. To characterize and emphasize this duality the term synarchic regulation is introduced to convey the notion that these messengers act together to rule the intracellular domain. Although this duality appears to be nearly universal, the pattern of Ca2+-cAMP interaction varies from cell type to cell type. At least five variations on the universal theme can be recognized: coordinate, hierarchical, redundant, antagonistic, and sequential. By viewing hormone action as a process of information transfer, it is possible to analyze the sequential steps in hormone action. The key features of cell activation are the rise in concentration of a second messenger (Ca2+ or cAMP) in the cell cytosol, recognition of this rise by a specific receptor protein leading to a binding of messenger to protein, and then the binding of this complex in turn to one or more response elements. The molecular basis of this process in the calcium messenger system has been described and the very important relationship of change in cellular calcium metabolism to the messenger role of (Ca2+)c has been emphasized. A distinction has been made between this process of amplitude modulation of cell function in the calcium messenger system, and the process of sensitivity modulation. This occurs by a mechanism that involves the activation of a calcium-calmodulin-dependent enzyme by changing its sensitivity to activation by Ca2+ rather than a change in (Ca2+)c. A common means by which sensitivity modulation takes place in the calcium messenger system is by a cAMP-dependent phosphorylation of a subunit of a calmodulin modulated response element. This type of sensitivity modulation provides molecular evidence in support of the concept of synarchic regulation.