Departments of Neurology and Psychiatry, Georg-August-University, and Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
THE PLAYERS WITHIN the astrocytic endothelin (ET)
system are known, but the rules of the game have been obscure. . . . The current article in focus by Blomstrand and collegues (Ref. 1, see
page C616 in this issue) may shed some light on the
physiological significance of the astrocytic ET system.
Primary astrocytes in culture spontaneously express almost all
constituents of the ET system, i.e., the peptides ET-1 and ET-3 (5,
18), the G protein-coupled receptors
ETA and
ETB (4, 11, 19), as well as
ET-converting enzyme activity (2). Astrocytes in vitro, however, have
always to be considered as being somewhat activated even under
"basal conditions" compared with "resting astrocytes" in
the brain. Accordingly, astrocytes in vivo express only low and hardly
detectable amounts of the various components of the ET system in the
"resting state" (6, 8, 16). This is markedly changed on
activation as follows: after ischemia, neurotrauma, or
inflammatory conditions of the brain, all components of the ET system
are distinctly demonstrable in astrocytes both by in situ hybridization
and immunohistochemistry (20). By this means, regional heterogeneity
among astrocytes is found with respect to the ET system in vivo. Such
heterogeneity can be confirmed in vitro and may reflect different
functional requirements of distinct brain areas that become most
obvious under activated conditions.
A particularly interesting aspect of ET biology is that the ET system
can behave completely differently in different cell types. After
neurotrauma, a downregulation of vascular
ETB receptors resulting in a loss
of ET-mediated vasodilation (9) is paralleled by a tremendous
upregulation of astrocytic ETB
receptors (21). In this condition, the astrocytic
ETB receptors could serve as targets for the increased levels of ET-3, the endogenous
ETB ligand. But brain injury
increases ET-1 levels as well, and ET-1, although a potent nonselective
agonist, binds to ETB receptors
with similar affinity. What sense does it make to have both ET peptides
around? The elevated levels of ET-1 and ET-3 may partly be derived from inflammatory cells but to a considerable extent also from astrocytes themselves. Why do astrocytes produce both peptides?
The work by Blomstrand et al. (1) may explain why and how the ratio of
ET-1 to ET-3 can modulate astrocytic function through subtle
alterations of the Ca2+ signal
pattern in single cells. In fact, ET-1 and ET-3 are shown by these
authors to induce intracellular
Ca2+ increases with different
response patterns, while exhibiting comparable inhibition of gap
junction permeability and comparable blockade of the propagation of
intercellular Ca2+ waves in
astrocytes. ET-1 and ET-3 thereby profoundly and variably influence
astrocytic communication, ranging from metabolic homeostasis to
potential propagation of apoptotic signals (22). The types of ET
binding sites involved as well as the ratio of extracellular ET-1 to
ET-3 concentration may determine the relative amount of cells
displaying a certain Ca2+
signaling pattern. Variability of the
Ca2+ signaling pattern in turn may
be of major functional relevance, since this has been found to modulate
efficiency and direction of gene transcription (3, 17). The interaction
of both ETA and
ETB receptors on astrocytes for
creating a certain Ca2+ response
pattern has also been demonstrated using cultures from ETB-deficient rats as a
subtraction model (7).
How are differential effects of ET-1 and ET-3 achieved? Astrocytes
express both ETA and
ETB receptors. Although the effect of ET-3, a predominant ETB
agonist, is entirely abolished by
ETB antagonists, the action of
ET-1 on astrocytes is by far more complicated. Only combined
application of ETA and
ETB antagonists is capable of
measurably competing with ET-1, i.e., reducing or abolishing its effect
in astrocytes, whereas each antagonist alone is inefficient. This has
been observed in binding assays (12), ET elimination experiments (10),
and, in the work of Blomstrand et al., both in gap junctional
permeability and intercellular
Ca2+ wave propagation experiments.
This phenomenon could be explained based on the assumption that the
ET-1 molecule can bind simultaneously to an
ETA site and an
ETB site. But how can such binding
take place? A potential clue has been delivered by recent work on other G protein-coupled receptors, the
ARTICLE
TOP
ARTICLE
REFERENCES
-aminobutyric acid B
(GABAB) and the
and
opioid receptors. Heterodimerization is required for the formation of a
functional GABAB receptor out of
per se nonfunctional GABAB
subunits (13, 15, 23). Heterodimerization, however, can also occur
between two fully functional G protein-coupled receptors, as shown for
the
and
opioid receptors (14), resulting in a "new"
receptor with ligand binding and functional properties distinct from
those of either receptor. Similarly, heterodimerization of
ETA and
ETB receptors in activated
astrocytes may mediate functional diversity on stimulation. ET-3 would
not be able to appreciably compete with ET-1 for binding to heterodimer
receptors, whereas competition for binding to monomeric
ETB receptors between ET-1 and
ET-3 would occur. Such "Lego-play" with receptor molecules may
represent additional and as yet unrecognized instruments in a powerful
concert of cellular interactions.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Ehrenreich, Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Str. 3, D-37075 Göttingen, Germany (E-mail: ehrenreich{at}exmax1.mpiem.gwdg.de).
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REFERENCES |
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