Calcium wave fronts that cross gap junctions may signal neuronal death during development

Abstract

Embryonic anterior pagoda (AP) neurons in the leech interact with their segmental homologs in adjacent ganglia through transient axons that overlap during a critical period of development and then retract. However, when an AP neuron is ablated mechanically or by irradiation during this period, an adjacent homolog responds by reinitiating growth of its overlapped axon and thereby taking over vacated territory (Gao and Macagno, 1987b; Gao, 1989). The death of an AP cell is therefore communicated to its homolog, but the mechanism underlying this signaling is presently unknown. Since it was recently found that AP homologs are electrically and dye coupled through their transient axons (Wolszon et al., 1994), we investigated the possibility that gap junctions may mediate the cell death signal that could occur between developing neurons. Among several candidate intercellular signals, we began by studying calcium dynamics in embryonic AP cells, in situ, since calcium is known to cross gap junctions and is implicated in cell death in many systems. We found that elements that usually increase [Ca2+]i in adult neurons, such as releasable internal stores or voltage-dependent calcium channels, were not present at the critical period. Instead, mechanisms that reduce free calcium, such as buffering and pumping, were the most robust. When a large, focal calcium rise was produced in an AP axon by making a lesion with a UV microbeam (leading to eventual death of these neurons), calcium did not rise quickly throughout the cell, but rather moved in a slow (0.05-0.25 micron/sec) wave front away from the lesion site, into other processes of the damaged cell. Furthermore, when a calcium wave front reached the growth cone of a transient axon, it crossed at the gap junctions into the coupled axon of the neighboring AP neuron, but went no further. Since it is known that an AP responds to a neighbor's death by reinitiating growth only in that axon that contacts the dying cell (Gao and Macagno, 1987b; Gao, 1989), these observations are consistent with calcium playing a role in the signaling of cell death to homologs that are coupled to a dying cell.

Gap junction intercellular communication propagates cell death in cancerous cells

“…generate a Ca 2+ wave. The possibility that Ca 2+ waves spread through gap junctions may kill cells has been shown before in a study on the development of neural tissue (Walszon et al, 1994). It is likely that the limitation of the size of the focus of dying cells is, at least partially, due to the relatively slow speed with which Ca 2+ waves spread through gap junctions (Jorgensen et al, 1997).…”

Endogenous Gradients of Resting Potential Instructively Pattern Embryonic Neural Tissue via Notch Signaling and Regulation of Proliferation

“…The integration of GJ dynamics with cellautonomous ion channel circuits to understand global bioelectric properties is a major area of future research (Palacios-Prado and Bukauskas, 2009). While the chemical nature of the GJ-permeable signal is not yet known, ideal candidates include serotonin (Fukumoto et al, 2005a;Levin, 2007) and Ca 2ϩ (Wolszon et al, 1994;Blomstrand et al, 1999).…”

Intercellular Ca2+Waves: Mechanisms and Function

“…The excessive elevation of [Ca 2ϩ ] i that is likely to be associated with these stimuli can lead to Ca 2ϩ -dependent PLC activation, the generation of large amounts of IP 3 , and the initiation of ICWs. Such ICWs may exacerbate injury by communicating signals that initiate cell apoptosis in surrounding cells (90,196,197,398). Recent evidence indicates that IP 3 diffusion via gap junctions is crucial to provoke apoptosis in adjacent cells (89).…”