Temporal relationship of the two phases

One of the ways in which integration to yield a monotonic response is achieved is through the initial calcium transient..As already discussed, the transient rise in intracellular calcium is responsible for stimulating calcium-calmodulin dependent kinases to bring about the initiation of the response. However, the magnitude of the sustained phase of the response also correlates with the magnitude of the initial calcium transient. Several lines of evidence indicate that this correlation reflects an effect of calcium on PKC activation. It has been demonstrated in studies with isolated red blood cell membranes that the amount of PKC which becomes associated 

In addition, a reciprocal interaction between the two phases occurs, in that PKC exerts important feedback effects during the sustained phase of the response. Since activation of PKC leads to an enhancement of calcium efflux and a reduction in the calcium concentration within the submembrane domain, PKC essentially limits its own activity. Furthermore, in adrenal glomerulosa and cultured vascular smooth muscle cells, PKC activation during the sustained phase acts as a feedback modulator of the initial transducing events. The artificial activation of PKC with phorbol esters prevents these initial events (the calcium transient and PIP2 hydrolysis) [59,60] yet at least in cultured smooth muscle cells PI hydrolysis is not blocked [30]. Thus, PKC activation may result in a shift in the substrate specificity of phospholipase C. 

This shift in the substrate specificity of phospholipase C may persist for some time after the removal of agonist and may contribute to the phenomenon of cellular memory in the adrenal. When glomerulosa cells are sequentially exposed to All (20 minutes)-, no agonist (10 minutes), and again All, the character of the response elicited by the second addition of All differs dramatically from that elicited by the first the cell seems to remember its prior exposure to All [29], Although this second addition of All induces a smaller calcium transient, the rate of aldosterone secretion increases more rapidly and reaches a higher plateau value than is seen in response to the first exposure to the hormone. This result suggests either that the second addition of All elicits a smaller increase in 1,4,5-IP3 as a result of an altered 

On the basis of results obtained from studies in adrenal glomerulosa, vascular smooth muscle and hepatic cells, it is evident that the major effects of All on cell function are mediated via an activation of the calcium messenger system. Furthermore, the data, although far from complete, provide convincing evidence that a temporal and spatial pattern of events underlies hormonal action. 

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