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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+-clearingmechanisms that return the [Ca2+]i to prestimulation 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+ handlingmachinery. 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 TRPMelastatin 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. [ABSTRACT FROM AUTHOR]

Introduction: Until recently, metabotropic glutamate receptor 4 (mGlu4) has not received adequate attention in terms of drug targeting when compared to other members of the same mGlu receptor family, possibly because of the difficulties encountered in developing highly selective, either orthosteric or allosteric, ligands for this receptor. Areas covered: This review gives to discussion to the past and recent advances (between 2012-2017) in targeting the mGlu4 receptor for the treatment of disorders of the central nervous system (CNS) as well as immunological (neuroinflammation) and metabolic diseases (diabetes). Chemical structures, properties, and pharmacological properties discussed herein were retrieved from the scientific literature databases, PubMed and Google Scholar. Expert opinion: The fertile field of mGlu receptor positive allosteric modulators (PAMs) has recently led to the discovery of foliglurax, a highly selective mGlu4 receptor PAM with optimal bioavailability after oral administration and excellent brain distribution. However, further elucidation of the biological properties of the mGlu4 receptor, including expression and its signalling profile in distinct tissues and cells are still awaited in order to establish the mGlu4 receptor as a definite drug target in several CNS and non-CNS diseases.