Signalling specificity in GPCR-dependent Ca²⁺ signalling

Cells use signalling networks to translate with high fidelity extracellular signals into specific cellular functions. Signalling networks are often composed of multiple signalling pathways that act in concert to regulate a particular cellular function. In the centre of the networks are the receptors that receive and transduce the signals. A versatile family of receptors that detect a remarkable variety of signals are the G protein-coupled receptors (GPCRs). Virtually all cells express several GPCRs that use the same biochemical machinery to transduce their signals. Considering the specificity and fidelity of signal transduction, a central question in cell signalling is how signalling specificity is achieved, in particular among GPCRs that use the same biochemical machinery. Ca²⁺ signalling is particularly suitable to address such questions, since [Ca²⁺]_i can be recorded with excellent spatial and temporal resolutions in living cells and tissues and now in living animals. Ca²⁺ is a unique second messenger in that both biochemical and biophysical components form the Ca²⁺ signalling complex to regulate its concentration. Both components act in concert to generate repetitive [Ca²⁺]_i oscillations that can be either localized or in the form of global, propagating Ca²⁺ waves. Most of the key proteins that form Ca²⁺ signalling complexes are known and their activities are reasonably well understood on the biochemical and biophysical levels. We review here the information gained from studying Ca²⁺ signalling by GPCRs to gain further understanding of the mechanisms used to generate cellular signalling specificity.