Biomedical Engineering Reference
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cone closer to the cathode promoting preferential growth toward the cathode
(Figure 18.5 A).
18.6.4 Calcium
Calcium seems to play a very important role in the mechanism of growth cone
turning; substantial research by McCaig et al. has led to such a hypothesis: “Cath-
odal turning requires infl ux of Ca
2+
via voltage - gated Ca
2+
channels (VGCC) and
Ca
2+
release from ryanodine and thapsigargin-sensitive intracellular stores. Acti-
vation of AChRs (yellow) by spontaneous release of Ach (green) induces cyto-
plasmic Ca
2+
elevation further, since the receptors are 'leaky'” to Ca
2+
. Activation
of the trkC and trkB receptors is also required for cathodal turning. Addition of
NT-3, the ligand for the trkC receptor (blue) or brain-derived neurotrophic factor
(BDNF), the ligand for the trkB receptor (magenta) to the culture medium
enhances the cathodal response. This implicates the AChR further because NT-3
and BDNF stimulate release of ACh from the growth cone, therefore enhancing
the asymmetric signaling via AChRs at the cathodal side of the growth cone. trkB
receptors and AChRs activate the phospholipase C (PLC), phosphatidylinositol
3-kinase (PI-3K) pathway, elevating intracellular Ca
2+
even further. Ca
2+
eleva-
tion stimulates cAMP production via adenylate cyclase. cAMP activates the
protein kinase C-dependent kinase (PKA), which affects signaling by the rho
family of small GTPases (rac1, rhoA, and cdc42).
Activation of rac1 and cdc42 by PKA stimulate lamellipodial and fi lopodial
formation, respectively. This is hypothesized to underlie the EF-stimulated orien-
tation of fi lopodia and lamellipodia on the cathode-facing sides of growth cones,
which are essential for cathodal orientation. Inhibition of rhoA by PKA activa-
tion cathodally prevents cathodal growth cone collapse, but relatively low levels
of PKA signaling anodally permit rhomediated growth cone collapse, further
enhancing growth cone asymmetry. This leads to asymmetric tension within the
growth cone and turning toward the cathode. (McCaig et al. 2005) (Figure 18.5B)
Support for this theory can be visualized using fl uorescent Ca
2+
labeling within
growth cones (Figure 18.5C and D). When exposed to an EF of 120 mV/mm, the
Ca
2+
present in the growth cone increases (Figure 18.5D), compared to the little
Ca
2+
prior to EF exposure (Figure 18.5C).
18.7 NEURAL PROGENITOR CELLS AND ELECTRIC FIELDS
NPCs share some characteristics with neurons; some of the same receptors and
ion channels may be affected by an EF. One example is the TrkB signaling cascade,
which is known for promoting differentiation of neural progenitor cells (Sieber-
Blum 1991). Changes in these or other membrane bound proteins may infl uence
the TrkB cascade or other signaling cascades, causing changes in differentiation,
such as the preferential adoption or increase in a specifi c cell fate over another
when NPCs are exposed to an EF. Another example is bFGF, which is known to
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