Intercellular Ca(2+) waves: mechanisms and function

Abstract

Intercellular calcium (Ca(2+)) waves (ICWs) represent the propagation of increases in intracellular Ca(2+) through a syncytium of cells and appear to be a fundamental mechanism for coordinating multicellular responses. ICWs occur in a wide diversity of cells and have been extensively studied in vitro. More recent studies focus on ICWs in vivo. ICWs are triggered by a variety of stimuli and involve the release of Ca(2+) from internal stores. The propagation of ICWs predominately involves cell communication with internal messengers moving via gap junctions or extracellular messengers mediating paracrine signaling. ICWs appear to be important in both normal physiology as well as pathophysiological processes in a variety of organs and tissues including brain, liver, retina, cochlea, and vascular tissue. We review here the mechanisms of initiation and propagation of ICWs, the key intra- and extracellular messengers (inositol 1,4,5-trisphosphate and ATP) mediating ICWs, and the proposed physiological functions of ICWs.

Figure 1.

Examples of intercellular Ca²⁺ waves (ICWs) in cell cultures. A: an ICW in C6 glioma cells transduced to express the gap junction connexin, connexin (Cx) 26. The ICW was initiated by the focal photolytic release of inositol 1,4,5-trisphosphate (IP₃) within a cell (panel 2s) at the location indicated by the star symbol. B: an ICW in rat brain endothelial cells (endogenously expressing Cx37 and Cx43) induced by exposure of the cells to extracellular Ca²⁺-free conditions. Dimension bars = 50 μm. Color bar indicates change in fluorescence level. An increase in fluorescence represents an increase in [Ca²⁺]_i. Sample time of each panel is indicated in seconds.

Figure 2.

Basic mechanisms driving a diffusive Ca²⁺ wave across a cell (either initiating or communicating the wave; see sect. III). Inositol 1,4,5-trisphosphate (IP₃) diffuses across the cell and binds to an IP₃ receptor (IP₃R) to stimulate Ca²⁺ release from the endoplasmic reticulum (ER). The positive feedback (+ve) of Ca²⁺ on the IP₃R initiates Ca²⁺-induced Ca²⁺ release (CICR) through the IP₃R. The elevated [Ca²⁺]_i has a negative feedback (−ve) on the IP₃R to terminate CICR and limit the [Ca²⁺]_i increase. Some Ca²⁺ may diffuse to adjacent ryanodine receptors (RyR) to initiate CICR via these receptors. However, IP₃ diffusion occurs more quickly than Ca²⁺ diffusion (due to cytosol protein buffers) and propagates the Ca²⁺ wave more efficiently. IP₃ may have been produced in response to cell stimulation or may have entered the cell via a gap junction.

Figure 3.

Overall hypothesis for the communication of ICWs. Local stimulation (see sect. II) can lead to elevated IP₃ in the initiator cell. As IP₃ diffuses across this cell, it generates an intracellular Ca²⁺ wave by the release of Ca²⁺ through IP₃Rs with amplification from RyRs. Diffusion of IP₃ through a gap junction to an adjacent cell initiates a second intracellular Ca²⁺ wave, via IP₃Rs and RyRs. In addition, or alternatively, the stimulated cell releases ATP (in either a Ca²⁺-dependent or -independent manner) via plasma membrane channels (hemichannels, maxi-anion channels) or vesicular release. The extracellular diffusion of ATP (or other messengers; see sect. IVB4) to adjacent cells activates P₂ receptors which, in turn, stimulate IP₃ production to generate a Ca²⁺ signal in the adjacent cell. Propagation may involve the regenerative release of ATP (see sect. VIB). Each mechanism can occur in isolation or synergistically.

Figure 4.

Overview of mechanisms and functions of intercellular Ca²⁺ waves (ICWs), based on ex vivo and in vivo evidence from the organs indicated. ICWs between cells of the same type are indicated by circular arrows; noncircular arrows indicate ICWs between different cell types. Gap junctions (GJs) and paracrine purinergic signaling (PPS) are involved in most cases, but only the most prevalent mechanism is depicted. Dashed arrows indicate proposed functions (in italics). Retina: ICWs that propagate in astrocytes and Müller cells may provoke electrical activity in retinal ganglion cells (RGCs) and influence the blood vessel caliber. Retinal pigment epithelium cells (RPE) show ICWs which may influence proliferation and differentiation of neural progenitor cells (NPCs). Cochlea: ICWs in supporting cells may be involved in K⁺ recycling and may influence outer hair cells (OHCs) via ATP release to alter the cochlear amplifier gain and inner hair cells (IHCs) to modify electrical activity and synaptic connectivity during development. Blood vessels: ICWs propagate along the vessel wall via endothelial cells (ECs) and modulate white blood cell (WBC) interactions with ECs as well as smooth muscle cell (SMC) contractility via direct (myoendothelial gap junctions) or indirect mechanism to control vessel diameter. Brain: mechanisms of ICW propagation differ with brain region; GJs, GJs+PPS, or PPS mediate ICWs in the neocortex, hippocampus, and corpus callosum and Bergman glia, respectively. ICWs of astrocytes propagate via astrocyte endfeet to small-diameter blood vessels to influence blood vessel diameter. ICWs of astrocytes may also modulate synaptic signaling as well as contribute to neural development or disease processes (AD, Alzheimer disease; CSD, cortical spreading depression). Liver: ICWs propagating between hepatocytes may influence hepatic glucose output, bile production, and tissue regeneration.