The very close interdependence of Ca2+ and hormones in the overall metabolism of cyclic nucleotides has recently been emphasized by Cheung. Clearly the results presented here show that [Ca2+] in the physiological range (less than 10(-7) M to greater than 10(-6) M) has profound effects on the activity of adenylate cyclase from both brain and cardiac muscle. Whereas both brain and cardiac cyclase exhibit a Ca2+ dependent inhibition (perhaps mediated by calmodulin), only the brain cyclase is activated by Ca2+ via calmodulin. With both cyclases there is an inverse relationship between the inhibition of cyclase and the activation of calmodulin dependent (cAMP and cGMP) phosphodiesterase as a function of Ca2+ concentration. Because the IC50's for Ca2+ are the same in both heart and brain, the possibility exists that the Ca2+ inhibitory site of both cyclases is similar and perhaps identical. Considering the ability of Ca2+ to both stimulate and inhibit cyclase, one could imagine that in different species, tissues, or regions of the same tissue, there could exist multiple populations of cyclase, that is a cyclase which would only show Ca2+ dependent inhibition, Ca2+ dependent stimulation, or the biphasic response to Ca2+ (FIGURE 7). The fact that Ca2+ still regulates adenylate cyclase after various stimuli (histamine, NaF, etc.) suggests that Ca2+ may function to regulate the cyclase over shorter time periods (regardless of its state of stimulation) and that other affectors of cyclase (e.g., hormones) would serve to regulate the cyclase over longer time periods.