EDITORIAL FOCUS
The never-ending pas de deux
Focus on
"Capacitative Ca2+ entry is
involved in cAMP synthesis in mouse parotid acini"
Françoise
Pecker and
Jacques
Hanoune
Institut National de la Santé et de la Recherche
Médicale-Unité 99, Hôpital Henri Mondor, 94010 Créteil, France
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ARTICLE |
FOR WHAT SEEMS LIKE EONS, adenosine
3',5'-cyclic monophosphate (cAMP) and
Ca2+ have been competing for
supremacy in cellular signaling. They still are.
A study by Watson et al., the current article in focus (Ref. 8, see p.
C557 in this issue), brings new insight to the sophisticated control of
adenylyl cyclase by Ca2+. The
authors show that, in the parotid gland, activation of the enzyme is
governed by Ca2+ routed via the
capacitative Ca2+ channels.
Contrary to voltage-dependent Ca2+
channels and ligand-gated cation channels, which are expressed only in
selected sets of cells (neurons, myocytes, endocrine cells),
capacitative Ca2+ entry channels
are ubiquitous. These latter channels are activated by stimuli that
cause Ca2+ depletion of
endoplasmic/sarcoplasmic reticulum stores. Under physiological
conditions, their activation is preceded by inositol 1,4,5-trisphosphate
(IP3)-induced increases in
free intracellular Ca2+ concentration
([Ca2+]i).
There is little information as to how or by what mechanisms the
capacitative Ca2+ channels are
activated: various models have been proposed based on diffusible
factors or protein-protein interactions (for reviews see Refs. 1 and
4). The molecular identity of these channels is still questioned; the
finding that the transient receptor potential (trp) gene product in
Drosophila photoreceptors can function
as such a capacitative Ca2+ entry
channel may help in the elucidation of the mechanism of capacitative
Ca2+ entry (2).
With the use of HEK-293 cells, Fagan et al. (3) have expressed types I
and VIII adenylyl cyclases, which, according to in vitro studies, were
deemed to be activated by submicromolar Ca2+. It was shown that, in situ,
these isoforms of adenylyl cyclase do not sense elevations of cytosolic
Ca2+
([Ca2+]i)
due to Ca2+ release from
intracellular stores, triggered by either thapsigargin or ionophore. In
contrast, the isoforms are stimulated by the capacitative entry of
Ca2+ linked to the depletion of
internal stores (3). The authors noted that the efficacy of activation
of adenylyl cyclase promoted by
Ca2+ entry was particularly
striking compared with that promoted by Ca2+ release, in light of the
higher
[Ca2+]i
that was achieved by release compared with entry. Fagan et al.
concluded that adenylyl cyclase is compartmentalized in specific domains together with the capacitative entry channels and that Ca2+ entering the cell by other
means or Ca2+ released in the
cytosol does not have access to those domains. It should be pointed out
that, in the study by Fagan et al. (3) as well as in the present study
by Watson et al. (8), the cAMP increase in response to carbachol is due
not only to the capacitative Ca2+
influx but also to Ca2+ released
from intracellular stores. Ca2+
release evoked by carbachol occurs through specific
IP3 receptors, whereas
Ca2+ release evoked by either
thapsigargin or ionophore is rather nonspecific and involves
Ca2+ entry pathways other than
those regulated by IP3 receptors.
Taking into account that the parotid cells display a particularly high compartmentation of the internal
Ca2+ pool (6), it is tempting to
propose that IP3 receptors are also localized in the capacitative
Ca2+ influx/adenylyl cyclase
domains. Such a compartmentation is reminiscent of the cAMP
compartmentation produced on
-agonist stimulation reported
in myocytes (5). This stimulation causes a local activation of L-type
channels, leading in turn to inhibition of the neighboring types V and
VI adenylyl cyclases (9).
Overall, the study by Watson et al. (8) provides a direct demonstration
that capacitative Ca2+ influx can
increase cellular cAMP in native cells. However, a specific aspect of
this study should be noted: the
Ca2+-promoted increase in cAMP is
observed only in conditions in which cellular cAMP is already elevated,
i.e., in the presence of isoproterenol or in the presence of
phosphodiesterase inhibitors. This is similar to the conditions in
which activation by Ca2+ of type
III adenylyl cyclase is observed: in contrast with the activation of
types I and VIII, activation of adenylyl cyclase type III
by Ca2+ occurs only when the
enzyme is stimulated by other factors (e.g., forskolin, isoproterenol).
Watson et al. (8) propose that capacitative Ca2+ entry augments cAMP via the
activation of type VIII adenylyl cyclase, since this isoform is
expressed in parotid acini. However, the possible participation of
other isoforms cannot be eliminated at this point. Furthermore, the
fact that Sakai and Ambudkar (7) have shown that, in parotid acini,
regulation of Ca2+ influx by
Ca2+ store depletion involves
phosphorylation-dephosphorylation mechanisms might explain the
differences in Ca2+ influx
responses observed in basal and activated conditions.
If compartmentation of the signaling pathways is to be the final
conclusion of the Ca2+-cAMP
interplay, this is perhaps not unexpected, especially given the
increasing recognition of subcellular organization of signaling pathways. However, unequivocal evidence for such organization of
Ca2+ entry channels and adenylyl
cyclase isoforms has yet to be demonstrated.
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AJP Cell Physiol 274(3):C555-C556
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