Figure 15–31 Positive and negative feedback produce Ca2+ waves and oscillations. This diagram shows IP3 receptors and ryanodine receptors on a portion of the ER membrane: active receptors are in green; inactive receptors are in red. When a small amount of cytosolic IP3 activates a cluster of IP3 receptors at one site on the ER membrane (top), the local release of Ca2+ promotes the opening of nearby IP3 and ryanodine receptors, resulting in more Ca2+ release. This positive feedback (indicated by positive signs) produces a regenerative wave of Ca2+ release that spreads across the cell (see Figure 15–30). These waves of Ca2+ release move more quickly across the cell than would be possible by simple diffusion. Also, unlike a diffusing burst of Ca2+ ions, which will become more dilute as it spreads, the regenerative wave produces a high Ca2+ concentration across the entire cell. Eventually, the local Ca2+ concentration inactivates IP3 receptors and ryanodine receptors (middle; indicated by red negative signs), shutting down the Ca2+ release. Ca2+-pumps reduce the local cytosolic Ca2+ concentration to its normal low levels. The result is a Ca2+ spike: positive feedback drives a rapid rise in cytosolic Ca2+, and negative feedback sends it back down again. The Ca2+ channels remain refractory to further stimulation for some period of time, delaying the generation of another Ca2+ spike (bottom). Eventually, however, the negative feedback wears off, allowing IP3 to trigger another Ca2+ wave. The end result is repeated Ca2+ oscillations (see Figure 15–32). Under some conditions, these oscillations can be seen as repeating narrow waves of Ca2+ moving across the cell.
Another important property of IP3 receptors and ryanodine receptors is that they are inhibited, after some delay, by high Ca2+ concentrations (a form of negative feedback). Thus, the rise in Ca2+ in a stimulated cell leads to inhibition of Ca2+ release; because Ca2+ pumps remove the cytosolic Ca2+, the Ca2+ concentration falls (see Figure 15–31). The decline in Ca2+ eventually relieves the negative feedback, allowing cytosolic Ca2+ to rise again. As in other cases of delayed negative feedback (see Figure 15–18), the result is an oscillation in the Ca2+ concentration. These oscillations persist for as long as receptors are activated at the cell surface, and their frequency reflects the strength of the extracellular stimulus (Figure 15–32). The frequency, amplitude, and breadth of oscillations can also be modulated by other signaling mechanisms, such as phosphorylation, which influence the Ca2+ sensitivity of Ca2+ channels or affect other components in the signaling system.
The frequency of Ca2+ oscillations can be translated into a frequency-dependent cell response. In some cases, the frequency-dependent response itself is also oscillatory: in hormone-secreting pituitary cells, for example, stimulation by an extracellular signal induces repeated Ca2+ spikes, each of which is associated with a burst of hormone secretion. In other cases, the frequency-dependent response is non-oscillatory: in some types of cells, for instance, one frequency of Ca2+ spikes activates the transcription of one set of genes, while a higher frequency activates the transcription of a different set. How do cells sense the frequency of Ca2+ spikes and change their response accordingly? The mechanism presumably depends on Ca2+-sensitive proteins that change their activity as a function of Ca2+-spike frequency. A protein kinase that acts as a molecular memory device seems to have this remarkable property, as we discuss next.
Ca2+/Calmodulin-Dependent Protein Kinases Mediate Many Responses to Ca2+ Signals