Crosslink between calcium and sodium signalling

New Findings: What is the topic of this review? This paper overviews the links between Ca²⁺ and Na⁺ signalling in various types of cells. What advances does it highlight? This paper highlights the general importance of ionic signalling and overviews the molecular mechanisms linking Na⁺ and Ca²⁺ dynamics. In particular, the narrative focuses on the molecular physiology of plasmalemmal and mitochondrial Na⁺–Ca²⁺ exchangers and plasmalemmal transient receptor potential channels. Functional consequences of Ca²⁺ and Na⁺ signalling for co-ordination of neuronal activity with astroglial homeostatic pathways fundamental for synaptic transmission are discussed. Abstract: Transmembrane ionic gradients, which are an indispensable feature of life, are used for generation of cytosolic ionic signals that regulate a host of cellular functions. Intracellular signalling mediated by Ca²⁺ and Na⁺ is tightly linked through several molecular pathways that generate Ca²⁺ and Na⁺ fluxes and are in turn regulated by both ions. Transient receptor potential (TRP) channels bridge endoplasmic reticulum Ca²⁺ release with generation of Na⁺ and Ca²⁺ currents. The plasmalemmal Na⁺–Ca²⁺ exchanger (NCX) flickers between forward and reverse mode to co-ordinate the influx and efflux of both ions with membrane polarization and cytosolic ion concentrations. The mitochondrial calcium uniporter channel (MCU) and mitochondrial Na⁺–Ca²⁺ exchanger (NCLX) mediate Ca²⁺ entry into and release from this organelle and couple cytosolic Ca²⁺ and Na⁺ fluctuations with cellular energetics. Cellular Ca²⁺ and Na⁺ signalling controls numerous functional responses and, in the CNS, provides for fast regulation of astroglial homeostatic cascades that are crucial for maintenance of synaptic transmission.