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-beta pathway in rat myometrium: downregulation of Gqalpha /G11alpha "

Jeffrey R. Jasper

Department of Molecular Pharmacology, Roche Bioscience, Palo Alto, California 94304-1397

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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 Gqalpha /G11alpha 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-beta 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 Gqalpha /G11alpha . Interestingly, activation of G proteins via AlF-4 also decreases subsequent inositol phosphate responses and induces downregulation of Gqalpha /G11alpha . Hence, persistent activation of Gqalpha /G11alpha 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 beta -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 beta -adrenergic receptors by prolonged beta -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.

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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, Gialpha 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-beta pathway in rat myometrium: downregulation of Gqalpha /G11alpha . 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 alpha  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 Gqalpha and G11alpha 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
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society




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