Thirty years of Ca2+ spark research: digital principle of cell signaling unveiled

Abstract

Calcium ions (Ca²⁺) are an archetypical and most versatile second messenger in virtually all cell types. Inspired by the discovery of Ca²⁺ sparks in the 1990s, vibrant research over the last three decades has unveiled a constellation of Ca²⁺ microdomains as elementary events of Ca²⁺ signaling and, more importantly, a digital-analog dualism as the system design principle of Ca²⁺ signaling. In this brief review, we present a sketchy summary on advances in the field of sparkology, and discuss how the digital subsystem can fulfill physiological roles otherwise impossible for any analog system. In addition, we attempt to address how the digital-analog dualism endows the simple cation messenger with signaling speediness, specificity, efficiency, stability, and unparalleled versatility.

Keywords: Ca2+ microdomain; Ca2+ signaling; Digital system design.

Figure 1

Ca²⁺ sparks. A Two-dimensional confocal images of Ca²⁺ sparks in a quiescent cardiac myocyte (scan rate 1.0 s/frame). B Line-scan confocal images of an action potential-elicited [Ca²⁺]_i transient (top) and a spontaneous spark (bottom) (scan rate 2.0 ms/line). Time and space ordinates are displayed in the horizontal and vertical directions, respectively (Cheng et al. 1993)

Figure 2

Exemplary Ca²⁺ signaling microdomains. Cartoon illustration of various microdomains featured in different types of cells, all being artificially integrated in a hypothetical single cell. (1) Cardiac dyad. Single LTCC openings generate Ca²⁺ sparklets to activate a RYR2 Ca²⁺ nanospark in the cleft and a Ca²⁺ spark of 2 μm diameter in the surrounding space, as well as a Ca²⁺ blink in the connected ER/SR cistern. (2) Skeletal muscle triad (half structure illustrated). Arrayed RYR1 is mechanically gated by DHPR acting as the voltage sensor to initiate SR Ca²⁺ release, which, in turn, may activate nearby RYR3/β array via the CICR mechanism. (3) Subsurface cistern, to support subsurface sparks seen in smooth muscle cells and DRG neurons. (4) Clustered Orai1 and STIM1 forming an elemental unit for SOCE. Its digital operation gives rise to Ca²⁺ glows which morphology and kinetics are shaped by membranous structures like invadopodia. (5) Multimodal Ca²⁺ signaling microdomain. In human lung fibroblasts, Ca²⁺ flickers arise from both TRPM7 Ca²⁺ influx, sensing mechanical signals, and IP₃R Ca²⁺ release, sensing chemotactic signal mediated by platelet-derived growth factor receptor (PDGFR) signaling pathway, and dynamically regulate the assembly and disassembly of cytoskeletal filaments, and thereby steer the direction of cell migration. (6) Mitochondria-associated membranes (MAMs), the contact sites between mitochondria and ER, are a central hub for Ca²⁺ signaling, apoptosis, autophagy and lipid biosynthesis. (7) ER surface Ca²⁺ microdomains, sites of phase separation of protein complex for specification of autophagosome initiation. (8) Perinuclear Ca²⁺ waves from the ER in the nuclear envelope, with high Ca²⁺ passing through the nuclear pores. (9) Golgi Ca²⁺ microdomain