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.