Our overarching research in cell signalling is to understand how the Ca2+ ion, as the most common signal transduction element, can specifically control a myriad of cellular processes, and how drugs may modify these.
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 bind to and open specific ion channels on Ca2+-storing organelles to release their Ca2+ content and thereby produce complex Ca2+ signalling patterns. It is the pattern in time and space of the Ca2+ signal that ultimately determines which cellular responses are recruited.
During cellular communication, a multitude of extracellular signals are transduced to kinetically (and spatially) variable intracellular Ca2+ signals in various subcellular cellular compartments that dictate changes in cell responses.
Extracellular signals are coupled to subcellular Ca2+ signals via diffusible intracellular messengers and their targets. These messengers are synthesized and metabolized under control of stimuli-regulated enzymes, and each messenger acts on its own cognate Ca2+-release channel family located on organelles to orchestrate distinct Ca2+ signaling patterns. The ability to ‘mix-and-match’ multiple messenger combinations in response to different stimuli allows the cell to generate specific spatially and temporally unique Ca2+ signals, which in turn are decoded to specify distinct cellular responses. The cracking of this “calcium code” requires a detailed understanding of the spatial and temporal dynamics of the messengers, proteins and organelles that interplay to act as Ca2+ signal pattern generators.
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 we have shown that it evokes Ca2+ release from organelles of the “acidic’ endo-lysosomal system: a new role for these important organelles. My recent work has also highlighted the role of a novel family of endo-lysosomal channels, the two-pore channels (TPCs) in NAADP-mediated Ca2+ signalling.
Endolysosomal-based NAADP-mediated Ca2+ release is now recognized as a widespread trigger for intracellular calcium signalling, and studies of TPCs have enhanced our understanding of this process. This mechanism is now known to underpin or modulate fundamental pathophysiological cellular processes as diverse as Ebola virus disease infection, fertilization 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, and may offer new targets for therapeutic intervention in a variety of diseases.
We use molecular and optical techniques to measure and manipulate endolysosomal Ca2+ signals to understand their role in health and disease.