Intracellular Ca²⁺ signalling: unexpected new roles for the usual suspect

Cytosolic Ca²⁺ signals are organized in complex spatial and temporal patterns that underlie their unique ability to regulate multiple cellular functions. Changes in intracellular Ca²⁺ concentration ([Ca²⁺]_i) are finely tuned by the concerted interaction of membrane receptors and ion channels that introduce Ca²⁺ into the cytosol, Ca²⁺-dependent sensors and effectors that translate the elevation in [Ca²⁺]_i into a biological output, and Ca²⁺-clearing mechanisms that return the [Ca²⁺]_i to pre-stimulation levels and prevent cytotoxic Ca²⁺ overload. The assortment of the Ca²⁺ handling machinery varies among different cell types to generate intracellular Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ release through Transient Receptor Potential Mucolipin 1 (TRPML1); 2) Endoplasmic reticulum-to-mitochondria Ca²⁺ 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 Ca²⁺ signals in the cardiovascular system.