Intracellular Ca(2+) signalling: unexpected new roles for the usual suspect

Cytosolic Ca(2+) signals are organized in complex spatial and temporal patterns that underlie their unique ability to regulate multiple cellular functions. Changes in intracellular Ca(2+) concentration ([Ca(2+)](i)) are finely tuned by the concerted interaction of membrane receptors and ion channels that introduce Ca(2+) into the cytosol, Ca(2+)-dependent sensors and effectors that translate the elevation in [Ca(2+)](i) into a biological output, and Ca(2+)-clearing mechanisms that return the [Ca(2+)](i) to pre-stimulation levels and prevent cytotoxic Ca(2+) overload. The assortment of the Ca(2+) handling machinery varies among different cell types to generate intracellular Ca(2+) signals that are selectively tailored to subserve specific functions. The advent of novel high-speed, 2D and 3D time-lapse imaging techniques, single-wavelength and genetic Ca(2+) indicators, as well as the development of novel genetic engineering tools to manipulate single cells and whole animals, has shed novel light on the regulation of cellular activity by the Ca(2+) handling machinery. A symposium organized within the framework of the 72nd Annual Meeting of the Italian Society of Physiology, held in Bari on 14–16th September 2022, has recently addressed many of the unexpected mechanisms whereby intracellular Ca(2+) signalling regulates cellular fate in healthy and disease states. Herein, we present a report of this symposium, in which the following emerging topics were discussed: 1) Regulation of water reabsorption in the kidney by lysosomal Ca(2+) release through Transient Receptor Potential Mucolipin 1 (TRPML1); 2) Endoplasmic reticulum-to-mitochondria Ca(2+) transfer in Alzheimer’s disease-related astroglial dysfunction; 3) The non-canonical role of TRP Melastatin 8 (TRPM8) as a Rap1A inhibitor in the definition of some cancer hallmarks; and 4) Non-genetic optical stimulation of Ca(2+) signals in the cardiovascular system.