Calcium (Ca2+) is familiar as a structural component of teeth and bones, but has a more fundamental role in intracellular signalling as the universal regulator of cellular functions. Multiple small messenger molecules target specific ion channels on organelles to evoke the complex Ca2+ signalling patterns that determine the specificity of this ion in controlling an enormous array of cellular responses.
My overarching research question in cell signalling is how the Ca2+ ion as the most common signal transduction element can specifically control a myriad of cellular processes. During cellular communication, a multitude of extracellular signals are transduced to kinetically variable intracellular Ca2+ signals of variable magnitude in various subcellular cellular compartments that dictate changes in cell responses.
The three major messengers regulating Ca2+ signaling are inositol trisphosphate (IP3), cyclic ADP-ribose (cADPR) and nicotinic adenine dinucleotide phosphate (NAADP). Whilst IP3 and cADPR activate Ca2+ release channels of the “neutral” endoplasmic reticulum (ER), NAADP is unique in that it evokes Ca2+ release from organelles of the “acidic’ endolysosomal system: a new role for these important organelles. My recent work has highlighted the role of a novel family of endolysosomal channels, the two-pore channels (TPCs) in NAADP-mediated Ca2+ signalling.
In this talk, I will discuss the role of lysosome-based NAADP-mediated Ca2+ release as a widespread trigger for intracellular calcium signalling and how studies of TPCs have enhanced our understanding of this process.
This work has informed fundamental pathophysiological cellular processes as diverse as Ebola virus disease infection, fertilisation and embryology, cardiac contractility, T cell activation and neuronal excitability. The discovery of lysosomes as calcium stores mobilized by NAADP has identified an entirely new signalling role for these organelles in health and disease.