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Hallett, M.B. Localisation of the Ca2+ Signal for Phagocytosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/40925 (accessed on 23 July 2024).
Hallett MB. Localisation of the Ca2+ Signal for Phagocytosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/40925. Accessed July 23, 2024.
Hallett, Maurice B.. "Localisation of the Ca2+ Signal for Phagocytosis" Encyclopedia, https://encyclopedia.pub/entry/40925 (accessed July 23, 2024).
Hallett, M.B. (2023, February 07). Localisation of the Ca2+ Signal for Phagocytosis. In Encyclopedia. https://encyclopedia.pub/entry/40925
Hallett, Maurice B.. "Localisation of the Ca2+ Signal for Phagocytosis." Encyclopedia. Web. 07 February, 2023.
Localisation of the Ca2+ Signal for Phagocytosis
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24032825

Phagocytosis is one of the most polarised of all cellular activities. Both the stimulus (the target for phagocytosis) and the response (its internalisation) are focussed at just one part of the cell. At the locus, and this locus alone, pseudopodia form a phagocytic cup around the particle, the cytoskeleton is rearranged, the plasma membrane is reorganised, and a new internal organelle, the phagosome, is formed. The effect of signals from the stimulus must, thus, both be complex and yet be restricted in space and time to enable an effective focussed response. While many aspects of phagocytosis are being uncovered, the mechanism for the restriction of signalling or the effects of signalling remains obscure.

phagocytosis Ca2+ phospholipids

1. Diffusion of Chemical Signals

An important concept in understanding the mechanism of localised intracellular signalling is diffusion. Diffusion is, of course, the net movement of ions or molecules from a zone of higher concentration to one of lower concentration. Thus, if an intracellular signal is generated within the cell at the contact point between the phagocytic target and the plasma membrane of the phagocyte, its intracellular concentration will be higher at that point than elsewhere in the cell and diffusion of the signal molecules away from the point of contact will occur. Diffusion is, of course, the result of the random Brownian motion of individual ions or molecules, causing the initial concentration of signals to be “diluted out” as molecules move away from a source. Although random at an individual ion/molecule level, the net effect occurs in a predictable way and the concentration can be calculated at any point distant from the source as it declines with passing time [1]. The decrease in concentration of a molecule depends on its distance from the source of the signal (the contact between the target and the cell), the time elapsed (t), and its diffusion constant (D, μm2/sec).
The equations which govern these relationships, especially in two and three dimensions, can look daunting [1], but the main parameter which governs the process is the diffusion constant, D, a measure of “diffusivity” of the molecule or ion in a given environment. A simple, but useful, approach for estimating how a localised focal signal may be restricted is to calculate its “diffusion length” given by:
2 √(Dt), where D is the diffusion constant (μm2/s) and t is the time (s) taken. The concept of diffusion length applies to both ions in solution and to lipids in a membrane.

2. Theoretical Basis of Localisation of Ca2+ Signalling

Phagocytosis by opsonised particles is accompanied by Ca2+ influx from the extracellular environment generating intracellular Ca2+ signalling [2][3]. The earliest report of phagocytosis by neutrophils showed that Ca2+ in the medium was an absolute requirement for phagocytosis [4]. However, an intracellular Ca2+ signal may not always be obligatory, and there are early reports using nonopsonised particles in which no Ca2+ signals were found [5][6]. Indeed, the phagocytic cup can partially form without any Ca2+ signal [7][8]. However, when a critical number of opsonin receptors have been engaged (often about 50% of the cup), Ca2+ influx is triggered, causing a large cytosolic Ca2+ signal [7]. This Ca2+ signal accelerates the rate of completion of phagocytosis and probably accounts for the increased phagocytic rate caused by opsonisation observed in cell populations. The flattening and spreading of neutrophils onto surfaces, which may be considered as “frustrate phagocytosis”, is also accompanied by obligatory large Ca2+ signals [9][10]. The Ca2+ signal can be thought of as being the permissive signal for efficient phagocytosis.
As suggested earlier, in considering the question of whether this Ca2+ signal could be localised to the site of phagocytosis, a useful parameter is the “diffusion length” which indicates how far from the source of the signal Ca2+ ions would travel by a defined time. The diffusion length can be calculated from knowledge of the diffusion constant, D, as 2√(Dt. The diffusion constant for Ca2+ in water, DCa, has been measured as 7.7 × 10−6 cm2/s [11]. i.e., approximately 800 μm2/s. The diffusion length of Ca2+ ions after 100 ms (0.1 s) would thus be 2√(800 × 0.1) = 18 μm. As this is larger than the diameter of many phagocytes (e.g., neutrophils are about 10 μm), it suggests that Ca2+ ions are unlikely to act as a localised phagocytic signal. However, the diffusion constant for Ca2+ (DCa) in extracted cytosol is lower and has been measured, using Ca45 at 530 μm2/s [12], 223 μm2/s in cytosolic extract from Xenopus oocytes [13], or in living cells using fluorescence correlation spectroscopy at 650 μm2/s [14]. Thus, in the cytosol, the diffusion length of free Ca2+ is about 9.2–16 μm, which is still too large to generate localised Ca2+ signals. However, in the cytosol, Ca2+ ions bind reversibly to Ca2+ buffering agents, such as proteins and other molecules. It is estimated from the association rate (“on rate” or Kon) and buffer concentration that the lifetime of a free Ca2+ ion would be in the order of 10−5s [13], meaning that the free unbuffered Ca2+ signal would be extremely localised. However, the buffer molecule is also mobile and will diffuse, carrying Ca2+ with it until the ion is released. It is, thus, more appropriate to consider the diffusion of buffered Ca2+ ions. The measured diffusion constant for buffered Ca2+ is higher than for free cytosolic Ca2+ and the diffusion length of the buffered Ca2+ is extended from d1 to (d1 + d2). For Ca2+ -binding proteins with the EF hand-motif (e.g., calmodulin, calbindin, etc.), the dissociation rate (koff) is about 10 s−1, giving a “lifetime” of the Ca2+–buffer complex of 0.1 s (100 ms). The diffusion constant of the buffered Ca2+ has been measured in cytosol extract to be 13 μm2/s. After 100 ms (when the Ca2+ ion is released), the diffusion length is only about 2.3 μm [13]. Assuming that the released Ca2+ ion is free for about 1 s before being taken up into immobile Ca2+ stores, the “effective range” of buffered Ca2+ is about 5 μm [14]. Although these measurements were made using cytosol extract with a Ca2+-buffering content of about 300 μM [13], the Ca2+-buffering ratio of neutrophil cytosol is similarly high, about 1000-3000:1 [15][16], meaning that for every free Ca2+ ion in the cytosol, there are 1000-3000 bound Ca2+ ions, so the conclusion can be extrapolated to neutrophil cytoplasm. The diffusion length predicted can also be experimentally confirmed in neutrophils by osmotically lysing Ca2+-containing lysosomes to release a small localised Ca2+ signal in the cytosol. This is achieved by the use of a dipeptide glycyl-l-phenylalanine 2-naphthylamide (GPN), which is cleaved within cathepsin C-containing lysosomes and is widely used to osmotically rupture the lysosomal membrane and release its Ca2+ content into the cytosol. In neutrophils, this procedure generated “Ca2+ puffs” with diameters of about 3 μm [17], similar to those expected from the theoretical diffusion length calculation for buffered Ca2+. This suggests that the localisation of Ca2+ signals during phagocytosis is at least theoretically possible in neutrophils and probably other phagocytes. However, as the influx of Ca2+ from the extracellular environment is the important Ca2+ source for phagocytosis, understanding the mechanism for generating the Ca2+ signal is crucial.
The diffusion length of free Ca2+ is very small (d1), as Ca2+ ions are rapidly bound to proteins (buffers). However, the buffer also diffuses (d2), carrying the Ca2+ ion to be released at a different location. The time between the binding and release of the Ca2+ ion depends on the dissociation rate (koff or off rate), during which time the buffered Ca2+ travels the distance d2. Ca2+-binding proteins have koff rates of about 10 s−1, giving a “lifetime” of 0.1 s. Hence, the diffusion length of the buffered Ca2+ is extended from d1 to (d1 + d2).
The classic initiation mechanism for Ca2+ signalling is via IP3, which is produced by the action of a phospholipase C on phosphatidylinositol 4,5-bisphosphate (PIP2) [18]. The two classes of “opsonin receptors” both activate PLCγ through tyrosine kinase receptors. These include the Fc receptors, triggered by antibody-opsonised targets and β2 integrin, triggered by complement (C3bi)-opsonised targets [19]. PLC β in neutrophils is also activated by G protein-coupled receptors for soluble agonists, such as formylated peptides. The activation of either PLC generates IP3, which diffuses from the plasma membrane away from the initiation site to engage IP3 receptors on Ca2+ storage sites throughout the cell. This releases Ca2+ from the Ca2+ stores, which in turn signals plasma-membrane-channel opening through a mechanism known as “store operated Ca2+ channel” (or SOCC) opening [20][21]. Unlike Ca2+, IP3 has a long effective range [13] of 24 μm (having both a higher diffusion constant, 283 μm2/s, and having no buffers). Thus, for cells smaller than 24 μm, IP3 will fill the cell and act as a global messenger, thus losing any directional information as to the locus of its formation at the phagocytic site.
Route (a) shows the effect of direct coupling of the stimulus to the opening of Ca2+ influx channels (here supposed to be the transient receptor potential cation channel, subfamily M, member 2, or TRPM2). Ca2+ influx from that site, with limited diffusion distances, would retain information as to its source. In contrast, (b) is the signal for Ca2+ via PLC. The generation of IP3 with its extensive diffusion would result in the opening of Ca2+ channels from remote Ca2+ storage sites in the cell, which would open store-operated Ca2+ channels (SOCC) in the plasma membrane at all loci and so lose directional information.
The mechanism by which store-operated Ca2+ Channels (SOCC) open when Ca2+ is depleted from the endoplasmic reticulum may involve the Orai1 and STIM1 system [22][23][24]. There is considerable evidence that the Orai–STIM system also operates in phagocytes [2][25][26] and is responsible for hotspots of high Ca2+ at the formed phagosome–cytosol boundary [27].
A Ca2+ influx mechanism which may not involve the depletion of Ca2+ stores or IP3 generation is the opening of TRPM2 channels (transient receptor potential cation channel, subfamily M, member 2), Ca2+-permeable channels which are highly expressed in phagocytic immune cells [28][29][30]. These plasma membrane channels, previously called LTRPC2 or TRPC7, are permeable to both Na+ and Ca2+ and may be involved in immune-cell behaviour including adhesion and migration [31]. TRPM2 is activated or directly opened by ADP-ribose (ADPR) as well as by oxidants (e.g., H2O2) [32]. There is evidence that neutrophils (and probably other phagocytes) utilise these Ca2+-signalling pathways [33][34][35]. Although the mechanism of activation of the channel or of the generation of ADP-ribose is not fully established, oxidants are known to open the channel directly and also to enhance the opening by ADPR [32]. As oxidants are generated locally within the phagosome, they may play a role in local TRPM2 opening through H2O2 signalling. The key point, however, is that since TRPM2 activation does not involve IP3 generation, there is at least a theoretical possibility that an opsonin-triggered Ca2+ signal could remain localised to within a few microns of the phagocytic contact site if TRPM2 channels were involved.

3. Localisation of Ca2+ Signalling of Phagocytosis

An early paper [36], using a single-wavelength Ca2+ reporter, Quin2, reported that Ca2+ signalling was highest in the pseudopodia and periphagosomal cytoplasm. Although fura2 was reported to give a similar result [37], persistent, localised, elevated Ca2+ during pseudopodia formation and the onset of phagocytosis cannot generally be confirmed using modern dual-wavelength or confocal imaging of a number of probes. The reported Quin2-elevated fluorescent signals in pseudopodia (i.e., prephagocytic structures) were probably the result of an optical effect whereby fluors are more efficiently excited and emission-detected in the less light-scattering cytoplasm of pseudopodia [38]. When followed in time, the Ca2+ signal which accompanies phagocytosis, although presumably triggered locally, causes a global elevation in cytosolic Ca2+ (14,16, 45). In one study [39], the question was addressed of whether the presence of the Ca2+ indicator itself affected the Ca2+ distribution by being an additional Ca2+ buffer with high mobility. The Ca2+ indicator (fluo4) was, therefore, chemically coupled to a large protein with low mobility and microinjected into neutrophils before phagocytosis. This indicator also failed to detect localised Ca2+ signalling. How, then, can Ca2+ signal the localised events that precede and trigger phagocytosis?
With this in mind, it is relevant that one of the many cytosolic targets of an elevated Ca2+ level has a very low affinity for Ca2+, the Ca2+-activated protein calpain. There is increasing evidence that calpain activity is involved in the formation of phagocytic pseudopodia [40]. For example, pharmacological inhibition of calpain slows phagocytosis by arresting the rapid phase of internalisation [7][9]. The outcome of calpain activation is the cleavage of ezrin, a protein which “staples” the cortical actin network to the plasma membrane [41], maintaining cell-surface wrinkles, which are a reservoir of extra membrane required for phagosome formation [41][42][43], and also regulates the cell-surface membrane tension [42][43][44]. After ezrin cleavage, there are fewer cell surface wrinkles as measured by SEM [45] or sub-domain FRAP (fluorescence recovery after photobleaching) [46] and, consequently, more membrane available for the formation of the phagosome [39]. Using constructs of ezrin with fluors attached to either side of the cleavage site (each with different excitation and emission properties), the cleavage of ezrin could be monitored by separation of the two fluors [47]. This method demonstrated that ezrin cleavage occurred in the phagocytic pseudopodia as it encroached around the target for internalisation [47]. The release of the plasma membrane from the actin cytoskeleton has also been observed in other cell types forming “cell protrusions”. Membrane-proximal F-actin, i.e., actin, held close to the membrane by crosslinking proteins was reduced at the loci of these cell protrusions in RPE-1 and HUVEC cells [48] and ezrin was decreased at similar protrusion sites in osteosarcoma cells [49]. Furthermore, in response to a photoactivatable ezrin phosphatase used experimentally to reduce the effectiveness of ezrin linking, the cell protrusion rate was increased, suggesting the release of a brake of the protrusion system [49].
While most Ca2+-activated cytosolic signalling proteins have kds between 0.1 μM and 1 μM, calpain-1 requires a Ca2+ level of 50–100 μM for activation [50]. For example, calmodulin, the ubiquitous Ca2+-regulated protein, has a kd for Ca2+ of about 0.3 μM, meaning that at the resting cytosolic Ca2+ level of 0.1 μM, calmodulin is not active, but when cytosolic Ca2+ rises to 1 μM, calmodulin becomes almost fully active. In contrast, calpain-1 has a kd for Ca2+ of about 30 μM, so that calpain in the bulk cytoplasm will remain inactive during the Ca2+ rise to 1 μM. The consequence of this is that calpain can only be activated very closely to the open Ca2+ channel or in a cell location where such a high Ca2+ level may be reached. One such location is within wrinkles of the plasma membrane, structures such as microridges. Phagocytes by necessity have such structures as these provide the membrane reservoir needed for the formation of the phagosomes [39][45][46]. It has been estimated that the neutrophils’ surface area has an excess of membrane, two to three times that required simply to enclose the cell volume [39][44]. From the modelling of Ca2+ influx into a confined volume of cytosol, it has been estimated that the Ca2+ concentration in the cytosol within the wrinkled membrane can reach hundreds of micromolar [51]. This is because open Ca2+ channels allow Ca2+ to enter the small volume of cytosol within the wrinkle at a faster rate than it can diffuse into the bulk cytosol through the “mouth” of the wrinkle [41][51]. Once the local Ca2+ buffers in the wrinkle space are overwhelmed, the free Ca2+ concentration can rise to very high levels. The intra-wrinkle Ca2+ has been recently measured using a construct, called EPIC3, from a low-affinity genetic Ca2+ indictor, CEPIA3 (kd for Ca2+ ≈ 11 μM), coupled to ezrin, which locates within the wrinkles and near the plasma membrane [52]. Upon phagocytosis, the intra-wrinkle Ca2+ was estimated to rise to 30–80 μM [52], sufficient to activate calpain, release ezrin, and uncouple the plasma membrane from the underlying actin cytoskeletal network [47][52].

4. Localisation of Ca2+ Signals after Phagocytosis

In contrast to the role played by Ca2+ in initiating phagocytosis, after a closed phagosome has formed, elevated periphagosomal Ca2+ may occur. It is possible that the phagosome itself provides the localised source of Ca2+ for this effect. This periphagosomal Ca2+ signal has been reported using the dual-excitation-wavelength probe, fura 2 [53], and more recently using the genetic Ca2+ reporter, GCaMP3, where a long-lived halo of elevated Ca2+ was detectable lasting over 6 min after phagocytic-cup formation [54]. Reported focal hotspots of Ca2+ (Ca2+ puffs) near phagosomes have also been visualised [27], which aid lysosome–phagosome fusion and also “boost phagocytosis” by recruiting Ca2+ stores near phagosomes [55].
The ion channels through which Ca2+ ions leak into the cytosol from the phagosome are probably TRPM2. These have been shown to be on the phagosomal membrane [56] and can be experimentally opened via the intraphagosomal microinjection of ADPR or H2O2 [56]. Since the intraphagosomal environment is oxidising (as a result of the NADPH oxidase) and contains H2O2 (the substrate for phagosomal myeloperoxidase), it seems likely that the channels are open and generate the elevated periphagocytic Ca2+ and periphagosomal Ca2+ hotspots observed. The roles of TRPM2 opening on the plasma membrane and on the phagosome are unclear, but since TRPM2 deletion increases susceptibility to polymicrobial sepsis without reducing phagocytosis itself [57], it would seem more likely that they have a role in postphagocytic events (e.g., lysosome fusion), rather than in signalling phagocytosis. It is obvious, in any event, that since these are postphagocytic events, they cannot be involved in signalling the phagocytosis event.

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Subjects: Cell Biology
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Maurice B. Hallett
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Update Date: 14 Feb 2023
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