EDITORIAL FOCUS
Stepping back and looking forward: downregulation of G
proteins as a mechanism of desensitization in tissues Focus on
"Carbachol-induced desensitization of PLC-
pathway in rat
myometrium: downregulation of
Gq
/G11
"
Jeffrey R.
Jasper
Department of Molecular Pharmacology, Roche Bioscience, Palo Alto,
California 94304-1397
 |
ARTICLE |
TACHYPHYLAXIS (desensitization) or waning of response
to prolonged or repeated agonist exposure is a fundamental observation in pharmacology and probably in numerous physiological settings as
well. Desensitization has been divided into agonist-specific (homologous) and agonist-nonspecific (heterologous) types. In the case
of many G protein-coupled receptors, homologous desensitization is
typically, at least in part, the result of a decrease in the number of
cell surface receptors ("downregulation") or in the efficiency of
receptor coupling to G proteins. It is less well appreciated that the desensitization process can also involve agonist-induced changes in the signal-transducing G proteins
(7). Thus G proteins may be translocated from the plasma
membrane to the cytosol or other intracellular organelles in response
to receptor activation (5, 9), the G protein associated with a receptor may be downregulated (i.e., degraded) (8, 11), or G proteins opposing
generation of the principal second messenger may actually be
upregulated (4). Such cross-regulation of G proteins greatly increases
the intricacy of control in signaling pathways and provides a mechanism
for heterologous desensitization (or supersensitization).
Although many years of research have been dedicated to understanding
tissue response to agonists and tachyphylaxis, most work addressing
control of cellular sensitivity at the molecular level has relied on
the use of clonal cell lines. Because the mechanisms for this
regulation vary among cell types (2), using clonal cell lines
simplifies the interpretation of results. Moreover, substantial recent
data have involved studies of transfected cell systems. However, the
relevance of results from clonal cell lines ("in vitro") and
transfected cell systems ("in transfecto") to mechanisms of
desensitization that are physiologically relevant ("in vivo") is
not always clear. Only recently have studies begun to concentrate on
the tissues in question rather than on a cell line overexpressing a
particular receptor or G protein of interest (10). As one moves away
from cell culture to assess mechanisms operative in native tissues, the
complexity increases but so too does the opportunity to identify cross
talk between different cell types that occurs in vivo. With the
application of appropriate technology, one has the potential to apply
information gleaned from the simplified cell systems to achieve a
unique and, one would hope, a more definitive and realistic
understanding of cellular communication.
In this regard, the current article in focus by Lajat et al. (Ref. 6;
see p. C636 in this issue) extends certain ideas to an in
vivo setting that heretofore have been primarily evaluated in cultured
cell models. Previous work from the authors' laboratory has provided
evidence for increased concentrations of
Gq
/G11
in the rat myometrium during gestation; this upregulation of G protein
correlates with enhanced phospholipase C (PLC) activity during late
pregnancy. The current article by Lajat and co-workers (6) extends the
previous findings regarding myometrial responsiveness but concentrates
on desensitization of the muscarinic cholinergic receptor
Gq/PLC-
3
cascade. The authors show that exposure of rat myometrium to the
agonist carbachol induces a rapid and prolonged decrement in
responsiveness to both muscarinic cholinergic stimulation (homologous
desensitization) and oxytocin receptor stimulation (heterologous
desensitization). Data are presented that support a role for protein
kinase C (PKC) in decreasing the receptor number on the plasma membrane
surface and that suggest this effect may account for the initial phase
of desensitization. By contrast, the later phase of
refractoriness appears to be independent of PKC and to involve
downregulation of
Gq
/G11
.
Interestingly, activation of G proteins via
AlF
4 also decreases subsequent
inositol phosphate responses and induces downregulation of
Gq
/G11
.
Hence, persistent activation of
Gq
/G11
can lead to heterologous desensitization of other hormone systems not
only by phosphorylation of the receptor via PKC but also through
decreases in G protein signaling (by an as yet unknown mechanism).
Changes in myometrial responsiveness during pregnancy and parturition
are well established. However, the mechanisms responsible for
maintaining a quiescent myometrium during pregnancy and those responsible for enhanced uterine contractility are still not clear. Intracellular calcium and cAMP often play opposing roles in the regulation of smooth muscle cells, including the myometrium. Thus changes in G protein-coupled receptors (e.g., oxytocin receptors) and
their cognate G proteins (e.g.,
Gq) almost certainly contribute to the control of myometrial responsiveness. It is easy to envisage the
delicate balance between pregnancy and parturition being disturbed by
changes in the signal transduction components due to disease or other
insults. Treatment of preterm labor has concentrated primarily on
blockade of oxytocin receptors (3) or activation of
-adrenergic
receptors (activating the cAMP response, which inhibits uterine
contractility) (1). Information accrued from current studies that G
proteins might be regulated via heterologous desensitization processes
in the myometrium makes one reconsider approaches to such tocolytic
(uterine relaxant) therapy. One could guess that desensitization of
-adrenergic receptors by prolonged
-agonist treatment might lead
to an even more sensitized myometrium. Would blockade of oxytocin
receptors (which activate the PLC pathway) lead to a sensitized
myometrium through upregulation of
Gq proteins? Do increased oxytocin
levels lead to a heterologous desensitization of the
Gq/PLC pathways in the uterus?
These questions remain to be answered, but the article by Lajat and
colleagues (6) is a step forward in our understanding of signal
transduction in the myometrium. Even more generally, the article raises
questions as to mechanisms of desensitization in vivo and the
possibility that changes in G protein expression may be more important
than previously suspected.
 |
REFERENCES |
1.
Boyle, J. G.
Beta-adrenergic agonists.
Clin. Obstet. Gynecol.
38:
688-696,
1995[Medline].
2.
Freedman, N. J.,
and
R. J. Lefkowitz.
Desensitization of G protein-coupled receptors.
Recent Prog. Horm. Res.
51:
319-351,
1996[Medline].
3.
Goodwin, T. M.,
R. Paul,
H. Silver,
W. Spellacy,
M. Parson,
R. Chez,
R. Hayashi,
G. Valenzuela,
G. W. Creasy,
and
R. Merriman.
The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human.
Am. J. Obstet. Gynecol.
170:
474-478,
1994[Medline].
4.
Hadcock, J. R.,
M. Ros,
D. C. Watkins,
and
C. C. Malbon.
Cross-regulation between G-protein-mediated pathways: stimulation of adenylyl cyclase increases expression of the inhibitory G-protein, Gi
2.
J. Biol. Chem.
265:
14784-14790,
1990[Abstract/Free Full Text].
5.
Haraguchi, K.,
and
M. Rodbell.
Isoproterenol stimulates shift of G proteins from plasma membrane to pinocytotic vesicles in rat adipocytes: a possible means of signal dissemination.
Proc. Natl. Acad. Sci. USA
87:
1208-1212,
1990[Abstract].
6.
Lajat, S.,
S. Harbon,
and
Z. Tanfin.
Carbachol-induced desensitization of PLC-
pathway in rat myometrium: downregulation of Gq
/G11
.
Am. J. Physiol.
275 (Cell Physiol. 44):
C636-C645,
1998[Abstract].
7.
Milligan, G.
Agonist regulation of cellular G protein levels and distribution: mechanisms and functional implications.
Trends Pharmacol. Sci.
14:
413-418,
1993[Medline].
8.
Mullaney, I.,
M. W. Dodd,
N. Buckley,
and
G. Milligan.
Agonist activation of transfected human M1 muscarinic acetylcholine receptors in CHO cells results in a down-regulation of both the receptor and the
subunit of the G-protein Gq.
Biochem. J.
289:
125-131,
1993[Medline].
9.
Ransnas, L. A.,
P. Svoboda,
J. R. Jasper,
and
P. A. Insel.
Stimulation of beta-adrenergic receptors of S49 lymphoma cells redistributes the alpha-subunit of the Gs protein between cytosol and membranes.
Proc. Natl. Acad. Sci. USA
86:
7900-7903,
1989[Abstract].
10.
Rubino, T.,
G. Patrini,
M. Parenti,
P. Massi,
and
D. Parolaro.
Chronic treatment with a synthetic cannabinoid CP-55,940 alters G-protein expression in rat central nervous system
Mol. Brain Res.
44:
191-197,
1997[Medline].
11.
Van de Westerlo, E.,
J. Yang,
C. Logsdon,
and
J. A. Williams.
Down-regulation of the G-proteins Gq
and G11
by transfected human M3 muscarinic acetylcholine receptors in Chinese hamster ovary cells is independent of receptor down-regulation.
Biochem. J.
310:
559-563,
1995[Medline].
Am J Physiol Cell Physiol 275(3):C634-C635
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