R
Preterm labour: a pharmacological challenge Andris Lbpez Bernal, G. Nicholas Europe-Finner, Sylvain Phaneuf and Stephen P. Watson Preterm labour is a major cause of perinatal mortality and morbidity, but its prevention most of the available
is difficult because
drugs lack uterine selectivity
have potentially serious side-effects the foetus. In this article, And&
for the mother or
16pez Bernal and
colleagues
discuss new evidence that shows
pregnancy
is associated
with changes in G protein
signalling and second messenger myometrium.
formation
in human
During gestation uterine relaxation
favoured by a pronounced thereby facilitating
increase
in Gas levels,
agents. Although it is not
that these changes in G protein function are
causally related to the spontaneous nevertheless increased
in
labour enabling the uterus to become
responsive to contractile established
is
the effect of agonists that increase
CAMP formation. The change in Ga, is reversed spontaneous
and
onset of labour,
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E
inflammatory drugs, Ca?+ channel antagonists) have bet n used in an attempt to inhibit preterm labour; however, tlie impact on the incidence of preterm delivery has bet n insignificant and most of the available drugs have pote.ltially serious side-effects for the mother or the infant. The prevention of preterm labour is made difficult n)t only by the inability to predict or even diagnose it, biit also by poor understanding of the regulation of myometrial contractility. Contractility in smooth muscle IS controlled primarily by [Cal+], and the extent of myosln light-chain phosphorylatio@. Increases in [Ca2+],can be achieved by Ca2+ entry into the cell through ion channels in the plasma membrane or by mobilizing Ca2+ from tile sarcoplasmic reticulum, for instance by the inositol(1,4,5)-trisphosphate [Ins(1,4,5)P,] receptor+fl. Contractions in human myometrium are phasic and mechanisms exist for the rapid lowering of [Ca2+],by extrusion of Ca !+ from the cells and by Cal+ uptake into the sarcoplasmlc reticulum. Relaxation can be achieved by lowering [Caz+], but also by lowering the sensitivity of myosin light-chain kinase to Ca?+, a process stimulated by the cyclic nucleotides CAMP and cGMP (Refs S-10). Uterine activity may be modulated by the autonomic nervous system (both adrenergic and cholinergic nerves are present), but since labour appears to be normal in paraplegic women and in women with bilateral lumbar sympathectomy, this appears to be of limited physiological importance.
they provide a novel viewpoint towards
understanding
of the cellular mechanisms
uterine contractility,
which may result in better drugs
for the management
of preterm labour.
of
The uterus has to serve two very different functions. For most of the 40 weeks of human pregnancy it is in a relaxed state and gradually increases in size to accommodate the growing foetus. However, at the time of parturition it has to contract regularly and forcibly to expulse the foetus through the birth canal. The factors controlling uterine relaxation during continuing pregnancy and the transition into uterine contractions at the onset of labour remain unknown. The last trimester of pregnancy is vital for the maturation of foetal organs in preparation for extra-uterine life. If this process is interrupted because of an early delivery, the chances of survival for the neonate are severely decreased. Preterm deliveries (deliveries before 37 weeks gestation) account for less than 7% of all deliveries, but they account for nearly 70% of perinatal deaths’. Moreover, although 50% of small preterm babies (weighing between 500 and 1000 g) now survive, there is a wide range of associated short- and long-term morbidity (respiratory disease, intracerebral haemorrhage) and the emotional trauma on parents and the burden on intensive care baby units is considerable. Preterm labour is a problem that affects both developed and underdeveloped countries and its prevention is a major aim of modern obstetrics”. Over the past 40 years a wide variety of drugs (e.g. P-adrenoceptor agonists, non-steroidal anti-
Is there an increase in stimulatory association with parturition?
pathways
in
The search for a ‘uterotonin’, which, when released IS responsible for the onset of labour, has been disappointing. A variety of agents have been investigated including oxytocin, eicosanoids, adrenoceptor agonists, endothelin, platelet activating factor, bacteria and cytokines, but none fulfil the criteria as the ‘trigger’ for parturition. The beststudied agents are oxytocin and prostaglandins, but other important agonists do exist (Table 1). Oxytocin stimulates contractility in human myometrium, both in k~ and ilz vitro, and is widely used alone or in combination with prostaglandins for the induction of labour. Oxytocin activates the inositol phospholipid pathway and increases [Ca2+], in human myometial cells”-13. The density of oxytocin receptors is higher in pregnant than in non-pregnant myometriumiki6 and it has been proposed that a premature increase in the density of myometrial oxytocin receptors could provoke preterm labour by sensitizing the uterus to relatively unchanged circulating levels of oxytocinr”. Oxytocin receptor antagonists (e.g. atosiban) decrease uterine activity significantly in women with threatening preterm labour” but their ability to prevent the onset of labour is not established. Human myometrium expresses prostaglandin EP and FP receptors18J9. Prostaglandin FP receptors are positively coupled to phospholipase C (PLC) and phospholipase A? (Refs 12,13), but there is no evidence for increased receptor density or increased coupling to PLC during
A. Lipaz Bernal. Lecturer. G. N. Europe-Firmer, Research Fellow. S. Phsneul, HPsearrh Fellnw Unlverslty 01 Oxlorrl Nufflrld Departrn~nt o mstmrs
and
Gynaerology
John
Aadrlllfe Hosp~fal Head,r,qm
Oxford
UK OX3 YDU. and s. P. Watson.
Lectuw uepamlent
01
Pharnracrllcgy III Oxlrrrd
UK (1x1 3OT
129
Umvm
Oxtoril,
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W
Table 1. Receptors involved in agonist-mediated control of uterine contractility Receptor
Pathway
Effect
Adrenoceptor 9 :iF
a2
ka2+ channel ?K+ channel ?AC &a2+channel
a2 a2 I32 P2
Contraction Contraction Relaxation Relaxation Relaxation Relaxation
at the onset of labour deserves further investigation. The use of selective EP, receptor agonists to inhibit preterm labour should be considered. Adrenoceptor agents have complex effects on myometrial contractility. For example, cx,-adrenoceptor agonists stimulate contractility by activating the inositol phospholipid pathwayzs. On the otherhand, B,-adrenoceptor agonists relax the uterus by stimulating CAMP production24. a,-Adrenoceptor agonists favour contractility by inhibiting CAMP formationzs, but could also promote relaxation by activation of K+ channels leading to hyperpolarization.
Peptide hormones OT V E{
2: ?PLC -1AC
ETi4 AT, AT,
:F
Prostanoid EP,
z? TPLC
Contraction Relaxation Contraction Contraction Contraction Contraction Relaxation Contraction
TPLC JAC
Contraction Contraction
2:
EP2
EPs EPs FP FP IP TP
Contraction Contraction Contraction Contraction Contraction Contraction
IF ?PLC
Muscarinic M, and M, M, and M, Others B2 B2
Iz
HI
?PLC ‘TAC
Hz
5-HT 5-HT PAF
1:: TPLC
Contraction Contraction Contraction Relaxation Contraction Contraction Contraction
AC, adenylate cyclase; PI.&. phospholipase AZ; PLC, phospholipase C; ‘? or 1 signifies that activity of signal transduction pathway is increased or decreased. Data modified from Ref. 1.
pregnancy or parturitionz0. Nevertheless, successful parturition is always accompanied by increased PGF,, production by decidualized endometrial and probably myometrial cells21.There is good pharmacological evidence for the existence of different prostanoid El’receptors in human myometrium: El’, and El’, receptors are stimulatory via activation of PLC while El’, receptors are inhibitory via stimulation of adenylate cyclase22.It is possible that other EP receptor subtypes are expressed in pregnant human myometrium. In some circumstances preterm labour appears to be a consequence of the premature release of prostaglandins and other inflammatory mediators in the decidua/foetal membranes area, triggered by infection (chorioamnionitis)i. The density of myometrial prostaglandin receptors does not increase towards term, but the possibility of a shift in prostaglandin signalling from inhibitory to stimulatory pathways
1 3
0
TiPS - April 1995 (Vol. 16)
Role of G proteins Many hormones that affect myometrial activation or relaxation bind to myometrial receptors coupled to heterotrimeric G proteins which regulate effector systems such as enzymes (e.g. adenylate cyclase, PLC) and ion channels. Because of the poor correlation between circulating hormone levels and the onset of uterine contractions it can be speculated that changes in the levels of myometrial G proteins may govern the state of uterine contractility. Thus, the onset of term or preterm labour may depend not so much on changes in the concentration of hormones reaching the myometrium, as on changes in their signal transduction pathways at the level of the G proteins, altering the balance of phosphoinositide metabolism and CAMPformation. In support of this suggestion, there is evidence from experiments in animals that changes in either the content, or function, or both, of G proteins in myometrium may influence uterine quiescence in pregnancy. In the rat, the cY,-subunit decreases significantly towards term and the CQ-and B-subunits increase at mid-gestation and return to normal levels at term26.In the same species the content of Go, in myometrial membranes increases at mid-gestation and decreases at tenS7. In the guinea-pig, the content of Gau,is higher in non-pregnant uterus than in pregnant uterus near term, and the opposite changes occur with GCX, and Go, levels28,whereas the content of Go+ is low in early pregnancy but increases near
[email protected], the coupling of G proteins to effector enzymes is altered during gestation. In the rat, myometrial adenylate cyclase activity in response to B-adrenoceptor agonists or PGE, appears to parallel the content of GuS isoforms in the tissue29.ln guinea-pigs, pregnancy provokes an increase in GTP-stimulated adenylate cyclase activity, with no changes in adenylate cyclase concentration, suggesting increased coupling of Ga, to adenylate cyclase30. Conversely, there is a decrease in GTP-stimulated phosphoinositide hydrolysis in pregnancy, suggesting an impaired coupling of G proteins (Go,,,,) to PLC (Ref. 31). Considerable caution must be shown in extrapolating these results to humans, but they indicate that during continuing pregnancy uterine relaxation is favoured by facilitating the effect of agonists that increase cAMP production, and by making the uterus less sensitive to hormones that stimulate the inositol phospholipid pathway.
x
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‘W
G protein changes in human myometrium: a role in parturition? Recently, an investigation into the expression of G proteins in human myometrium has demonstrated the presence of proteins from the G,, G, G, and G, type@*.Most of these G proteins are expressed at similar levels in pregnant and non-pregnant myometrium and the levels of (Y~,~~-, ai- and p-subunits are not altered by the presence or absence of labour. However, there is a marked increase in Ga, expression in pregnant, compared to non-pregnant tissue32.This increase involves both the large and short splice variants of Ga, and is evident in samples of myometrium obtained as early as 16 weeks gestation, with the levels remaining high in samples obtained at 3040 weeks gestation. These samples were obtained from donors who had undergone a caesarean section before the onset of labour (because of malposition of the foetus or other risks) or a pregnant hysterectomy for reasons unrelated to the onset of labour. However, when samples of myometrium were obtained during an emergency caesarean section (for foetal distress or malpresentation) following the spontaneous onset of labour, either preterm or at term, the levels of G~x~ were low, similar to the level in non-pregnant tissue33. In other words, the samples taken during the stage of uterine quiescence in pregnancy had high Ga, levels whereas when the women were in labour myometrial Ga, levels were low (Fig. 1). The functional consequences of the observed changes in GCX, expression have been studied by measuring adenylate cyclase activity in myometrial membranes33. Forskolin, which activates adenylate cyclase directly, increased CAMPformation to a similar level in pregnant and non-pregnant tissues, demonstrating a similar level of expression of adenylate cyclase under the two conditions. However, when myometrial membranes were stimulated with a GTP analogue there was an increase in adenylate cyclase activity which was significantly higher in pregnant than in non-pregnant tissue33. GTP-dependent adenylate cyclase activity decreased to non-pregnant levels in myometrium obtained in labour. Moreover, when myometrial membranes were challenged with PGE, in combination with GTP, there was a further increase in adenylate cyclase activity and the activity was again significantly higher in pregnant tissue not in labour than in either non-pregnant tissue or tissue in labour. These results demonstrate that increased GCX, expression in myometriurn during gestation results in enhanced CAMP formation. This effect is likely to be amplified by the progesterone-induced decrease in CAMP phosphodiesterase activity that occurs in human myometrium during pregnancy%. Increased Ga, levels favour uterine relaxation by increasing CAMP levels and, possibly, by inhibition of voltage-gated Ca*+ channel@. At the onset of labour, downregulation of GCL,results in decreased formation of &Ml’, loss of sensitivity to relaxing agonists, and a relative increase in responsiveness to contractile stimuli. This provides a mechanism for the onset of parturition which
kDa
kDa
: ,. .H”r,.&’ / I
-58
54-
1 Gas
; / !q
46-
-45
Fig.1.Detection of Gu, splice variants in human myometrium. Myometrial membranes were resolved by SDS polyacrylamide gel electrophoresls and Ga,was detected with antibody RM/l. Lane 1: non-pregnant; lane 2: pregnant not in labour; lane 3: term spontaneous labour: lane 4: spontaneous preterm labour. From Ref 33 with permission.
I
does not require changes in circulating levels of hormones. Furthermore, the downregulation of Gcx,is likely to occur over several hours, as indicated by antisense and receptor-stimulation studies in model cell linesx,37,thus providing a mechanism for the gradual increase of contractility before birth.
Regulation of G protein expression In rabbits, progesterone and oestradiol have opposing effects on G protein coupling to adenylate cyclase3*.In rats (a species with a clear progesterone fall and oestrogen surge before parturition), administration of progesterone in vim on Day 21 of pregnancy (close to the expected time of parturition) results in a significant increase in Gal, levels and in basal and cholera toxin stimulated adenylate cyclase activity27. These changes are blocked by the progestogen antagonist, mifepristone, and occur without apparent changes in myometrial Gal, mRNA levels, providing evidence of post-translational regulation of GCL, expression by progesterone. Oestradiol administration at the same stage of pregnancy in rats provokes a significant fall in Gcx, levels27. Corticosteroids are also known to regulate Ga, expression in a variety of rat tissues39. It is not known whether steroids have a similar effect on myometrial G protein expression in humans; however, the fall in myometrial GCK,levels in women in labour is unlikely to be a steroid-mediated event, because parturition occurs without apparent changes in oestrogens or progesterone levels in the peripheral circulation or in the myometriumx. Nevertheless, it is interesting to note that regular intramuscular administration of progesterone to women at risk of preterm labour results in significant prolongation of pregnancy in comparison to placebo-treated controls@, although progesterone is not effective in the inhibition of uterine contractions in active preterm labour.
Therapeutic implications The drugs most commonly used to inhibit preterm labour are P-adrenoceptor agonists and prostaglandin synthesis inhibitors, but there is no evidence that the use of these drugs decreases the incidence of premature delivery and there is some concern about potentially serious
TiPS -April
1995 (Vol. 16)
131
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v
E
quiescence
w
E
I
t
-
contractions
preterm labour has been introduceddl, but its efficacy and safety need to be tested by controlled clinical trials. Ion channels also represent an important target for drug interaction but a detailed discussion of this topic is beyond the breadth of this article. Ca*+ channel antagonists have been used for the management of preterm labour, but the available drugs lack myometrial selectivity. A recent study suggests that the Ca2+binding protein calbindin-D,, decreases significantly in the myometrium of women in spontaneous labour’*. The functional role of this protein is not known, but its disappearance may be associated with preterm labour. During labour there are changes in the Ca*+ dependence and voltage sensitivity of K+ channels in human myometrium43,g. K+ channel openers cause uterine relaxation by causing membrane hyperpolarization, but their effects are not specific for uterine smooth muscle.
Future perspectives
quiescence
w
t
contractions
t
contractions
quiescence
w
Selected references
Fig. 2. The balance between uterine quiescence and contractility a: Before implantation the uterus is in equilibrium between stimulatory (IP, and Caz+) and Inhibitory (Gu, and CAMP) pathways. b: During pregnancy the uterus stretches enormously to accommodate the growmg foetus. but it IS maintained in a quiescent state by the high level of Ga, expression which favours CAMP production by agonists, causing relaxation. c: The onset of labour may be a consequence of the fall in Ga, levels and the increased responsiveness of the myometrial myometrium to stimulatory agonists. IP,, inositol (1.4.5).trisphosphate.
side-effects (e.g. cardiovascular, gastrointestinal, renal) in the mother or in the foetus. However, these drugs are very useful to arrest preterm labour for a short time, when transport of the patient to a hospital with good neonatal facilities is necessary, or to allow the administration of glucocorticoids to accelerate foetal maturation. Recently, the use of a nitric oxide donor (glyceryl trinitrate) to arrest
1 3 2
Tip.5 - April
1995
(Vol.
16)
There is an urgent need to develop drugs with myometrial selectivity that allow long-lasting inhibition of labour and prolong pregnancy to a stage when good foetal maturation improves chances of survival. Available evidence suggests that parturition is the result of a switch from a pathway that favours uterine quiescence by increasing CAMP formation to a pathway that favours contractility through a relative increase in Ins(1,4,5)P, and [Ca*+li(Fig. 2). Nevertheless, it has yet to be demonstrated that this switch causes the onset of labour and is not merely associated with it. Further research is also required to elucidate the control of G protein expression and its functional coupling in human myometrium and to identify regulatory factors in the maternal or foetal compartments. There is no evidence that myometrial G proteins are uterine specific; however, increased understanding of their functional involvement in the regulation of uterine contractility should provide new approaches towards the development of better, more selective, drugs for the management of preterm labour.
1 Lbpez Bemal, A., Watson, S. I’., Phaneuf, S. and Europe-Firmer, G. N. (1993) Bailliere’s Clin. Obstet. Gynaecol. 7,523-552 2 Creasy, R. K. (1991) New En@ J. Med. 325,727-729 3 Allen, B. G. and Walsh, M. I’. (1994) Trends Biochem. Sci. 19,362-368 4 Szal, S. E. ~1al. (1994) Am. J Physiol. 267, ET-E87 5 Word, R. A., Stull, J. T., Casey, M. L. and Kamm, K. E. (1993) 1. Cfin. Invest. 92,29-37 6 Carsten, M. E. and Miller, J. D. (1990) in Uterine Function. Molecular and Cellular Aspects (Carsten, M. E. and Miller, J. D., eds), pp. 121-167, Plenum Press 7 Wray, S. (1994) Am. J. Physiol. 264, Cl-Cl8 8 Somlyo, A. I’. and Somlyo, A. V. (1994) Nature 372,231-236 9 Word, R. A., Casey, M. L., Kamm, K. E. and Stull, J. T. (1991) Am. /. Physiol. 260, C861-C867 10 Tang, D. C., Skull, J. T., Kubota, Y. and Kamm, K. E. (1992) 1. Biol. Chem. 267,11839-11845 11 Schrey, M. P., Comford, P. A., Read, A. M. and Steer, P. J. (1988) Am. J. Obstet. Gynerol. 159,964-970 12 Molnk, M. and Hertelendy, F. (1990) J. C/in. Endocrinol. Metab. 71, 1243-1250 13 Phaneuf, S. et al. (1993) J. Endocrinol. 136,497-509 14 Fuchs, A. R., Fuchs, F., Husslein, P. and Soloff, M. S. (1984) Am. J. Obskt. Gynecol. 150,734-741
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15 Rivera, J., L6pez Bemal, A., Vamey, M. and Watson, S. P. (1990) Endocrinology 127, 155-162 16 Kimura, T., Tanizawa, O., Mori, K., Brownstein, M. J. and Okayama, H. (1992) Nature 356,52&529 17 Goodwin, T. M. et al. (1994) Am. 1, Obsfet. Gynecol. 170, 474478 18 Hofmann, G. E., Rao, C. V., Barrows, G. H. andsanfilippo, J. S. (1983) 1. Clin. Endocrinol. Metab. 57,360-366 19 Adelantado, J. M., L6pez Bemal, A. and Tumbull, A. C. (1988) Br. 1. Obstet. Gynaecol. 95, 348-353 20 Word, R. A., Kamm, K. E. and Casey, M. L. (1992) 1. Clin. Endocrinol Metab. 75,1027-1032 21 Norwitz, E. R., Starkey, P. M. and L6pez Bernal, A. (1992) Obstet. Gynecol. 80,440-445 22 Senior, J., Marshall, K., Sangha, R. and Clayton, J. K. (1993) Br. 1. Pharmacol. 108,501506 23 Breuiller-Fouche, M., Doualla-Bell Kotto Maka, F., Geny, B. and Fern?, F. (1991) 1. Pharmacol. Exp. Ther. 258,82-87 24 Litime, M., Pointis, G., Breuiller, M., Cabrol, D. and Ferre, F. (1989) 1, C/in. Endocnnol. Metab. 69, l-6 25 Breuiller, M., Rouot, B., Litime, M. H., Leroy, M. J. and Ferre, F. (1990) 1. Chn. Endocrinol Metab. 70, 1299-1304 26 Tanfin, Z., Goureau, O., Mill&an, G. and Harbon, S. (1991) FEBS Lett. 278,4-S 27 Elwardy-MCr@zak, J. et al. (1994) 1. Mol. Endocrinol. 13,23-37 28 Warsop, H., Khouja, H., Wichelhaus, D. P. and Jones, C. T. (1993) J. Dru. Phywl. 19, 91-97
29 Cohen Tannoudji, J,, Vivat, V., Heilmann, J., Legrand, C. and Maltier, J. P. (1991) 1. Mol. Endocrinol. 6,137-145 30 Arkinstall, S. J. and Jones, C. T. (1990) 1. Endocrincll. 127, 15-21 31 Arkinstall, S. J. and Jones, C. T. (1990) Am. 1. Phys~ol.259, E57-Eh5 32 Europe-Firmer, G. N., Phaneuf, S., Watson, S. I’. and L6pez BemaP, A. (1993) Endocrinolppy 132,2484-2490 33 Europe-Firmer, G. N., l’haneuf, S., Tolkovsky, A. M., Watson, S. P. and L6pez Bemal, A. (1994) 1. C/in. Endocrinol. M&b. 79, 183.5-1839 34 Kofinas, A. D., Rose, J. C., Koritnik, D. R. and Meis, P. J. (1990) 1. Reprod. Med. 35,1045-1050 35 Khac, L. D., Mokhtari, A., Renner, M. and Harbon, S. (1992) Mel Pharmacol. 41,509-519 36 Wang, H. Y., Watkins, D. C. and Malbon, C. C. (1992) Nnfrrre 358, 334,337 37 Mill&an, G. (1993) Trends Pharmacol. Sci. 14,413-418 38 Roberts, J. M., Riemer, R. K., Bottari, S. I’., Wu, Y. Y. and Goldfien, A. (1989) 1. Dev. Physiol. 11, 125-134 39 Ha&h, R. M., Jones, C. T. and Milligan, G. (1990) \. Mol. Endocnnol. 5,185188 40 Keirse, M. J. (1990) Br. 1. Obstet. Gynaecol. 97, 149-154 41 Lees, C. et nl. (1994) Lancrt 343,1325-1326 42 Miller, E. K., Word, R. A., Goodall, C. A. and Iacopino, A. M. (1994) 1. C/in. Endocnnol. Metab. 79, 609-615 43 P@rez,G. J., Toro, L., Erulkar, S. D. and Stefani, E. (1993) Atn. I. Oh tef. Gynecol. 168,652460 44 Khan, R. N., Smith, S. K., Morrison, J, J, and Ashford, M. 1.. (1993) Proc. R. Sot. Londotl, Ser. B 251, 9-15
G protein-coupled P, purinoceptors: from molecular biology to functional responses
I’, purinoceptors, which regulate cellular function via G proteins. This terminology distinguishes these receptors from receptors for adenosine (also known as the I’, purinoceptors2). In 1985, Burnstock and Kennedy3 subdivided I’, purinoceptors into P2x and P,, on the basis of rank order of agonist potency; discriminating agonists included a&methylene ATP for I’, purinoceptors and 2-methylthioATP for Pzy purinoceptors (ATP is an effective agonist at both these subtypes). Given the continuing importance of agonist selectivity in the subclassification of I’, purinoceptors, it is surprising that recent evidence has cast doubt on the accepted generalization that 2-methylthioATP has a low potency at I’,, purinoceptors relative to that of a$-methylene ATP and P,y-methylene ATP (Refs 4,5). It is possible that rank order of agonist potencies has been confused by selective breakdown of 2-methylthioATP compared to a$-methylene ATP, and that inhibition of the breakdown of 2-methylthioATP reveals its true potency at P,, purinoceptordJ. Further subtypes have been described: for example, P2r purinoceptors (studied principally in platelets), at which ADP is an agonist and ATP is an antagonist; and I’,, purinoceptors (distributed widely), at which ATP and UTP are agonists, but a,&methylene ATP and 2-methylthioATP have no effect. UTP may also act at certain receptors not activated by purine nucleotides; however, these would not be classified as purinoceptors because UTP has a pyrimidine-based structure. Recently, a new nomenclature scheme has been proposed for I’, purinoceptor+ (for comment see Ref. 7), based on the predicted structure and the signal transduction mechanism. The influence of ATE’, ADP and UTP as extracellular messengers, therefore, extends beyond the material presented here, both with respect to other cells and tissues and with respect to actions at I’,, purinoceptors.
Michael R. Boarder, Gary A. Weisman, and Graeme F. Wilkinson
John T. Turner
Nucleotides
such as ATP and ADP act as intercellular
messengers
and exert a widespread
influence on
cellular function by acting on a variety of cell surface receptors.
Until recently, progress has been restrained,
in part, by a lack of cloned receptors. successful
Now, however, the
cloning of a variety of P, purinoceptors
holding out the prospect of rapid advances understanding
in the
of this diverse group of receptors
potent therapeutic article, Michael
resource they represent. Boarder and colleagues
is and the
In this
summarize the
findings of recent cloning studies, and assess the impact of these on the understanding the G protein-coupled
P, purinoceptors
of the function of in several types
of cells and tissues. A review of ATP and other nucleotides as intercellular messengers, including a discussion on the origins of extracellular nucleotides, has been published recently’. However, this article is concerned with those cell surface receptors for ATP, ADP and LJTP, referred to as
L?1995,
Elsrvicr
Science
Ltd
TIPS
Apnl
lYY5
(Vol
16)
Acknowledgements The authors acknowledge the fr,anclal suppolt of Arl~on Research-SPARKS and the MRC for the work quoted I” ttx review SPW IS a Royal Souety Unlverslty Researct1 FPlkw
M. R. Basrder, Senior Lecturer. Department of Cell Physolagy and Pharmacology. Un~versiry oi l.eicester Le1cestw UK LEl 9HN. C. A. Weisman, Assoaate Professor. Depanment of Biochemistry .I. T. Turner. Associate Professor Department of Pharmacology, Un~vewty of MISSOURIColumbia Columbia. MO 65212 USA antI G. F. Wilkinson. Postdoctoral Fellow Glaxo lnst~tute of Applied Pharmacology. Departmer of Pharmacology Uwers~ry of CambrIdge, ICambr,dge UK CB2 1OJ
133
