Biomedical Engineering Reference
In-Depth Information
Membrane-resident phosphoinositides, PIP
3
(14,26-28) and PIP
2
(29,18), are strongly polarized. In neutrophils, the gradient of the
marker for PIP
3
is six times the chemoattractant gradient (14) (Fig-
ure 2c).
At first sight, the strong polarization of phosphoinositides seems explicable
in terms of a simple amplification model. It suffices to postulate that phospho-
inositide synthesis responds to receptor activation in a highly cooperative man-
ner (Hill-type kinetics). In this case, the phosphoinositide distribution will be
similar in shape, but steeper in slope, when compared to the chemoattractant
concentration profile. The following observation precludes this simple model. If
a cell that is already polarized in a certain direction is exposed to a
modest
chemoattractant gradient along a different direction, a new phosphoinositide
localization and pseudopod does not develop at the point with the highest
chemoattractant concentration. Instead, the existing phosphoinositide localiza-
tion and pseudopod turn and reorient themselves along the new gradient
(14,25,30). It is as if the preexisting phosphoinositide localization and leading
edge is more sensitive to chemotactic signals than all other regions of the cell.
This phenomenon, called
polarized sensitivity
, suggests that during the course of
phosphoinositide localization at the leading edge a diffusible substance is
formed that rapidly migrates away from the leading edge and somehow inhibits
the generation of a new localization in other regions of the cell. Interestingly, if
the new chemoattractant gradient is relatively large and localized, the existing
localization dissolves and a new one grows at the maximum of the new gradient
(31,32,27).
Steady uniform chemoattractant concentrations
reveal two properties of
motile cells, namely,
spontaneous polarization
and
adaptation
.
When cells are exposed to such chemoattractant concentration profiles,
phosphoinositides accumulate uniformly along the entire plasma membrane
within 5-10 seconds. However, this uniform pattern does not persist for long.
Within a few minutes, the phosphoinositide distribution polarizes at a random
location. This phenomenon is called
spontaneous
polarization (33,34) to empha-
size the fact that the cells polarize even though the chemoattractant concentra-
tion is macroscopically uniform. The random location of the polarization
suggests that this phenomenon is stochastic in nature.
In
Dictyostelium
, the phosphoinositides return to their
pre-stimulus
uniform
distribution within 100-200 seconds (27), but the cells polarize eventually. It is
significant that phosphoinositides return to the pre-stimulus level even though
the chemoattractant concentration is several orders of magnitude higher than the
pre-stimulus level. This remarkable phenomenon is a manifestation of
adapta-
tion
(35). It follows that in
Dictyostelium
, the time scale of activation is 5-10
seconds, whereas the time scale of adaptation is 100-200 seconds. In neutro-
phils, the cells polarize spontaneously before there is any perceptible reduction
