Interactions between calcium and cAMP signaling

The calcium ion is quite possibly the single most pervasive signaling molecule used by living organisms for the purpose of communicating internal and external states. It differs from other messengers in that it is neither created nor destroyed, but just moved around inside and outside the cell via transporters, pumps and channels to alter its concentration in specific cellular locations. These changes in free [Ca(2+)] are then detected by a wide array of Ca(2+)-binding effector proteins whose affinities are appropriately tuned to respond to a particular type of [Ca(2+)] change. This deceptively simple paradigm dominates the function of many cell types, for example in driving contraction of muscle, action potential generation in nerves, fluid, hormone, and enzyme secretion in secretory cells, and certain immune responses. However, the Ca(2+) signal does not work in strict isolation, but rather is fine-tuned by many other signals, not the least of which is the other major second messenger, cyclic AMP (cAMP). Conversely, the cAMP pathway is subject to modification by the calcium signal and its various effectors at many different levels. These two fundamental second messengers, used throughout eukaryotes and even prokaryotes, are thus inextricably intertwined. The purpose of the present article is to provide an update on some of the recently described forms of reciprocal regulation between Ca(2+) and cAMP signaling circuits, with emphasis on interactions that take place in localized domains of the cell.