Tips - September 1989 [Vol. IO]
Roland Seifert and Gijnter Schultz
Uridine and uracil nucleotides are involved in the regulation of various cell functions. Here, Roland Seifert and Giinter Schultz review the evidence that, rather than by binding to purinoceptors, pyrimidine nucleotides exert their effects by binding to distinct pyrimidinoceptors, which are coupled to pertussis toxin-sensitive G proteins in human phagocytes. However, many questions remain to be answered: no antagonists for these pyrimidinoceptors are available, and binding studies have not been carried out; the receptor proteins and subtypes have not been characterized; and little is known about the G proteins and effector systems involved, or the regulation of storage and release of pyrimidine-nucleotides.
Extracellular adenosine and aden- ine nucleotides play an important role in the regulation of many cell functions13. Adenosine binds to adenosine Al or adenosine A2 receptors, leading to inhibition or activation of adenylyl cyclase and other effector systems regulated by guanine nucleotide binding proteins (G proteins)l. Extracel- lular adenine nucleotides bind to PZ purinoceptors which are sub- divided into Ph and PzY purino- ceptors according to the potency of purinergic agonists to activate cell funclions’~. In addition, cell type-specific purinoceptors have been described in mast cells and platelets*.
Occupation of purinoceptors with agonists results in the activa- tion of a variety of effector sys- tems such as phospholipase C, Ca*+ channels, superoxide- (O;-)- forming NADPH oxidase of HL-60 leukemic cells and n inhibition of adenylyl cyclaseP”. In the case of inhibition of adenylyl cyclase in rat hepatocytes and activation of phospholipase C and NADPH oxidase in HL-60 cells, purinocep- tors have been shown to couple functionally to pertussis toxin- sensitive G proteins4B*10*1’.
R. Seifert is P Research Fellow and G. Schultz is Professor at the Institut fiir Pkarmakologie, Freie IlMei;e?sitiit Berlin, Tkielallee 69173, D-1000 Berlin 33, FRG.
synergic regulation of cell It is known that extracellular uridine and uracil nucleotides are also effective activators of cell functions (Table I). However, rel- atively little attention has been paid to these observations. UTP is as effective as ATP in inducin relaxation of guinea-pig trachea l# . In addition, tixtracellular UTP re-
sults in dilatation of intra- and extracranial arteriess15. 6y con- trast, uracil nucleotides and uri- dine also effectively induce vaso- contraction and an increase in the systemic blood pressure13J4J~~.
These opposite effects of uracil nucleotides may be due to the fact that both vascular smooth muscle cells and endothelial cells are activated by LJTP. Thus, UTP may induce endothelium-depen- dent relaxation of blood vessels, presumably via the production of prostacyclin7*15,23. It has been sug- gested that the contraction of intracranial arteries by UTP plays an important role in tho patho- genesis of the vasospasm follow- ing cerebral injury, as platelets and brain tissue are rich sources of uracil nucleotides1s*21*z4~25.
The effects of extracellular uracil nucleotides are not restricted to the vasculature. UTP induces vari- ous metabolic changes in perfused rat liver, such as stimulation of tii release of _@ucose, K + and $*a It;
and mhibltlon of 4 uptake .
365 addition, UTP results in the mob- ilization of intracellular Ca*+ from non-mitochondrial stores and Ca*+ influx from the extracellular space in Madin-Darby canine kid- ney cells, Ehrlich ascites tumor cells, J774 macrophages and human neutrophils926B. In plate- lets and in neutrophils, uracil nucleotides induce aggrega- tion11*29j0. UTP activates O;- for- mation in HL-60 cells differen- tiated with dibutyryl cAl@O. In human neutrophils, UTP poten- tiates O;- formation and exocyto- sis of /%glucumnidase stimulated by formyl peptides%“. As pre- treatment with pertussis toxin inhibits UTP-induced O;- forma- tion in HL-60 cells and neutrophil aggregation, it is likely that the ,effects of UTP are mediated via G proteinslO*‘l. UTP also enhances retinoic acid-induced myeloid dif- ferentiation of I-IL-60 cel.ls31 F-zr- thennore, UTP and CTP ‘have recently been reported to activate phospholipase C in cultured rat anterior pituitary cell$*.
Differences between purlnergic and pyrimidinergic regulation
As there is no apparent stereo- chemical similarity between aden- ine and uracil nucleotides, the question arises whether the ef- fects of the uracil nucleotides are mediated via purinoceptors or via separate pyrimidinoceptors (Fig.
1). Forsberg et al.’ suggested that uracil nucleotides may bind to a subgroup of purinoceptors, whereas Martin et al.” suggested that certain purinoceptors also recognize pyrimidine bases.
These interpretations, however, are not very satisfactory, as only the stereospecificit-- of nucleotide receptors for purine bases would justify the term ‘purinoceptors’.
Indeed, there are several reports of dissociations between the ef- fects of extracellular adenine and uracil nucleotides, suggesting the existence of specific pyrimidino- ceptors (Table II).
o There are substantial differ- ences in ATP- and LJTP-induced contractions of intracranial and extracranial arteries with respect to desensitization, potency order of nucleotides, effects of various pharmacological agents and the release of 5-I-IT (Refs 16, 19 and 20).
e In perfused rat liver, there are
@j 1989, Ekevier Science Publishers Ltd. (VK) OMS- 6147/89/103.50
‘WS - Se~fe~ber 1989 WU~. 101 uracil nucfeotides
Arteries (various species) Dilatation (UTP, UDP) 13-15
Arteries (varfous species) untorn (UTP, UOP, UMP, urkiine. CTP) l3,14,162t
Portal vein (rat) Contraction (UTP, UDP, UMP) 16,22
Intact organism (various species) Increase of blood prsssure (UDP. UMP, uridine, UDP-glucose) 18 Endothelium (pig, Came) Formation of prostacyclin and inositolphosphates (UTP) 7,23 Liver(m) lnhibitfonofOeuptake,stfmulationofglucoseoutput, K+upfakeandreleaseof K+
and Ga** (UTP. UOP)
22
~~~y~ney~lls(d~~ Ca* fnfknr. int~llul~~z+ ~~liza~n (UTP) 29
~4m~a~(~) Ca2* inffux, fntracellufar Ca2+ mobffttation (UTP) 27
Ehrkich ascites tumor cells (mouse) Cae+ influx, intracellular Ca*+ mobilizatfon (UTP) 28
HL-99 cells (human) 0;-fomration,enhancementofdifferentiation(UTP) 1091
fUeutn#nils (human, rat) PotentiationofexocytosisandO~~ formation, aggregatfon,Ca2+influx(UTP) 9,l X30
P~~~(~rn~~ Aggregation (UDP) 29
~~~~(~t) Fowa~nof inosftol phosphates (UTP, CXP) 32
Most effective or potent pyrfmkfinergfo agonists are given in parentheses.
dissociations behveen the effects of ATP and UTP on several metab- olic parametenF.
e In HL-60 celki, the effects of Al? but not of IJ’W on NADPli oxidase or phospholipase C are partially resistant to inhibition by pertussin toxin, suggesting that purino- and Pyrimidinocepturs couple to different populations of G proteins~lO. In addition, ATP- induced activation of O;- form- ation in HL-60 cells is less sensi- tive to inhibition by activators of adenylyl cyclase than is the activa- tion induced by IJTP=‘.
@ In neu~p~s and J774 macro- phages, uracil nucleotides are more effective activators of certain cell functions than the corres- ponding adenine nucleotides11z7.
In J774 macrophages, ATP but not UTP induces a generalized in- crease in plasma membrane per- meability=. Activation of human neutrophils by purine nucleotides shows less pronounced base speci- ficity than the activation induced by pyrimidine nucleotides”. In addition, the effectiveness order of adenine nucleotides and the corresponding uracil nucfeotides to activate neutrophils is quite differenP.
Stereoselectivity of
pyrimidinergic cell activation One classical property of plasma membrane receptors is their abil- ity to discriminate stereoselec- tively various structurally related compounds. Figure 1 ihustrates the structur+activity relationship
for pyrimidinergic activation of NADPH oxidase in HL-60 cells.
The effects of pyrimidine nucleo- tides are ‘stereospecific with re- spect to the length and structure of the phosphate chain, to the sub- stitution of the ribose moiety and to the base. In most cell types examined so far, UTP is more effective than LIDI’, IJMP and uridine, and TIP and CTP are only relatively weak agonists. UTP induces dilation and contraction of blood vessels, whereas uridine exclusively induces contraction.
These data raise the ques- tion whether, like adenosine and adenine nucleotide receptors, uri- dine receptors are a class of recep- tor different from uracil nucleotide receptors. In addition, pyrimidinergic activation shows differencea in the nucleotide speci- ficity between different cell types, suggesting heterogeneity among pyrimidinoceptors. How- ever, pyrimidinergic activation of cell functions must be studied in much more detail, using a broad variety of pyrimidine nucieotides, before these questions can be answered definitely. These tasks may be facilitated by the use of phosphorothioate analogues uf uracil nucleotides; this technique has recently been used in the study of pyrimidinoceptors of human neutrophils”*.
Characterization of pyrimidinoceptors
So far, no antagonists for pyri- midinoceptors are available. In
addition, pyrimidinoceptors have not been characterized by binding studies, and the receptor proteins have not been identified.
At platelet purinoceptors the phosphomthioate analogues of GTP and GDP, guanosine 5’-O-(3- thiotiphosphate) and guanosine 5’-G-(2&iodiphosphate), am com- petitive antagonists of ADFss.
In the case of neutrophil pyri- midinoceptors, the corresponding phosphorothioate analogues of UDP and IJ’lT are agonists”. Aryl- azidoaminopropionyl ATP and adenosine 5’-[o&methylene]t- phosphate are antagonists at cer- tain puiinoceptors~. By analogy, the corresponding uracil nucleo- tides may be antagonists at pyri- midinoceptors.
The characterization of pyri- midinoceptors by receptor bind- ing studies will be a difficult task, as pyrimidine nucleotides appar- ently have rather low affinirf for their receptors. In addition, extra- cellular nucleotides including ura- cil nucleotides may rapidly be degraded by ectonucleotidases2, and recent evidence suggests that extracellular nucleoside triphos- phates are substrates for protein kinases catalysing the phos- phory]lation of several cellular pro- teins 5. At least for neutrophil nucleotide receptors, however, it is not likely that ~phosp~~~tion reactions catalysed by nucleoside diphosphate kinase are involved in regulation of cellular functions by extracellular purine and pyri- midine nucleotidesii.
TiPS - September 1989 [Vol. 201 Uridine 5’-[ar-35S-thio]triphos- phate and uridine 5’-[fl-35S-thio]-
~phosphate may be useful ligands for binding studies at certain pyri- midinoceptors, by analogy with the use of adenosine 51-[&%
thioltriphosphate and adenosine 5’-[35Sthio]diphosphate for the characterization of purinocep- tar?‘. Another possible approach would be to use stereospecific labelling of plasma membrane pro- teins to identify and to isolate the receptor proteins. Inte~stin~y, Tauber et al.ssobserved that labelled uridine and UTP covalently bind to specific plasma membrane pro- teins in rat liver. It remains to be determined, however, whether covalent binding of uridine and uracil nucleotides to proteins is causally linked to pyrimidinergic activation of cell functions, as acti- vation of NADPH oxidase in HL-60 cells by UTP is a reversible processlO.
Desensitization of
pyrimidinoceptors and receptor synergism
~sensitization of pyrimidino- ceptors has been shown for sev- eral cell types. In myeloid cells the mechanisms ~de~~ng desen- sitization of pyrimidinoceptors may be similar to those of formyl peptide receptors: cytochalasin B
367
Nucleotlde (-log M)
b:SbuchwmsofUTPderivaMnssandATP.UTPwasthemuFteffectiveandmastpotentof thepydmtdtnenucreorides testt.?d(t~5cur). Deaq4TPfdeo~~@~Wnsfeadof~~
Al~lers~~~~~CTPla~gmupinstead4fkg~Rin~~~ering
papifion 4j, ‘TTP MWhYl instead of hydmen, C, in pynmtdine rtng position 5) and UDP flacks the &mine1 phosphate gtvup, 0) am very paor ,+&om of NADpn ox&se.
PyrtmBceeptom in Ht-80 cells there&e sfemoseWW& mcvgnke the base, the rii moiety and tk potyphosphate chatn of pylimidine nucteot&s. fSw Ref. 10 for experimental details.)
potentiates the stimulatory effects
of both formyl peptides and UTP sion of plasma membrane recep- on O;- formation*“*3g, probably tom In human neutrophils and HL-60 cells cross-desensitization by preventing receptor sequestra-
tion and by enhancing the expres- between purinoceptors and pyri- midinoceptors occurslo*‘l. These
TABLE II. Differences between the effects of extracellular purtne and p~mi~ne nudeotMes on cett functions
ParaflWMr Puffne nucleotides Pyrlmldlne nucleotldes Ref.
Rabbit ear artery. wntxaotfon Pretreatment with [a,@CH&ITP Rabbit basilar artery, contraction
Treatment with p~~~i~ or react& btue B Pretreatment with ATP[YS]
Pretreatment with UTP
~~~I~~f~U~~~ wdlfatatfon
Antagonism by methysergfde or phentolamine, CHT release
Perfur& rat liver, varfoua metabolfc changes 0s consumption
Glucose output after withdrawal Initial K+ uptake
K+ release after wlthdrawal Ca*+ release
HL-MJ cells, CXs-f~~f~tatkfa Pertussis toxin sensitivity
Sensitivity to inhibition by CAMP-increasing agents Humah ueutrophlle, ~~~~on of
o;-
foraatfonSase specificity Effectiveness order
J774 maorophages, Cax+ inffux
Generalized increase in plasma membrane permeabilitV
desensttfzation
no effect desensitization no effect
yes
19 potent&ion/partial desensifbafion
20 e~~rn~t
no effect desensitization
14 no
incmase insist no
more effective
decrease Yes profonged Yes less effective
22
partial more resistant
complete more sensitive
ITP > ATP = GTP UTP > CTP. TTP inactive ATP[yS] > ATP 1 ADP > UTP[yS] > UTP = UDP[pS] =
(np)-ATP@S], ADP[ftS] inactive @p)-UTP[@], UDP inactive 10
11
Yes
27 no
[a,&CNslATP, adenosine 5’.[o;B-methylene]hiphosphate; ATP[yS], sdenosine 5’-O-[3-thiotrtphosphatel; ADPI@], adenosine 5’.0[2- thiocliphosphate]; (xp)-ATPMS], np-diastereomer of adenosine 5’.0[2-thiotriphosphate]; UTP[YS], uridine 5’.0[3-thiotriphwphate]; UDP[@S].
u&fine 5’-~[~t~~~ph~~te]; (np)-tITP[#tB], (~)~~s~r~rn~ of u&tine ~-~~-thio~p~~e]
368 TiPS - September 2989 [Vol. NJ]
to guanine nucleotides. The func- tional similarities between pur- inoceptors and pyrimidinoceptors make adenylyl cyclase, phospho- lipase C and Ca2’ and K+ channels likely candidates as pyrimidiner- gic effector systems.
Storage and release of pyrimidine nucleotides
Only limited information is available concerning the storage and regulation of release of uracil nucleotides. Uracil nucleotides are stored in granules of platelets and may be released from these cells upon stimulationz4. Uracil nucleo- tides are also present at concentra- tions of up to 0.7 umole g-l fresh weight in liver, kidney and brain=. By analogy with adenine nucleotides, uracil nucleotides may be released from cells under a variety of patholo~c~ conditions such as trauma, hypoxia and in- flammation2. Because uracil nu- cleotides activate cell functions in the concentration range 1 HAM to 1 mM, pyrimidinergic regulation is likely to take place in t&o. The question of whether there is a more specific and controlled re- lease of UTP into the extracellular space from intracellular stores of neurons, chromaffin or mast cells or from the cytosol deserves fur- ther investigation.
fomyl paWee UTP
cs2+
~.2~~~~~~~~~~e~h~an
m~&~Hcetts. Ce, cym&ak~ f3; DG. diacyfg&xW: G, Gptotein; FP, fot7nylpqtide m I&, ino&of t,4,M&phosphate; PKC, protein kinasa C: PLC, phospholipase C; PT. perto& toxin; PU, pwtmcspkx PY, pyrimidinw~. There an, several fon&mat similadtks in the eff&& of kxmyl pqtides and purine and pydmidine
of Ca2+, are
~,~~~~ deseosftization
andareinhfbitedbyanincraesainlfreintraaeiu~aDncentratianofcaMP(Flefs4-1 1). In add&on, their effeds am inhibited bypedu&s loxIn which ADP-dbasytates G pmteins, than&y htn&WMy unwupling mceph@vm t!mir e-r systems~io~ ’ ? Activation of
IS achievtxi erther di~,~~~~~~t~
-
~~~~~-es~~e
~thetdheeffedsofUTParemoresuscepfibietoinhibibbnbyperhrssisfoxinandan
inuease in CAMP than those of ATP and that the efkctiveness order of adenine .
ZiiWwlt
uckoMe3 aod the mnaqonding uracil nudeotides to activate ceil fonctions is quite rar’. Fudhennom, ATP and UTP potent&e the efkts of t&my1 peptide&‘?
results do not necessarily argue against the existence of different types of nucleotide receptor, but rather may support the concept that the two &asses of receptor are cl&y related functionally.
Different classes of intercellular signal molecule interact synergis- ticall
Y to activate human neutro- phils l. This is also the case for the interaction of pyrimidinoceptors and receptors for formyl peptides, platelet activating factor and leukotriene B4 to activate O;- formation, exocytusis and aggre- gation in human myeloid sellss-l*.
The mechanisms underlying sy- nergistic interaction of these re- ceptors may be complex. They may involve increases in the affin- ity of receptors, additive or syner- gistic activation of different pools of G proteins and amplified gen- eration of intracelh&r signal mol- ecules, such as diacylglycerol, Ca” and arachidonic acid. Study- ing the interactions of extracellu- lar pyrimidine nucleotides with Other intercelhtlar signal mol- ecules in non-myeloid ccl! types
should help elucidate the role of pyrimidines in regulating cell function.
Functional coupling to G prokins and effector systems
The characterization of the coupling of pyrimidinoceptors to G proteins is another important task. NADPH oxidase is coupled to pyrimidinoceptors via pertus- sis toxin-sensitive G proteinslo.
By analogy with purinergic activ- ation, pyrimidinergic activation of phospho~pase C in HL-60 cells is also likely to be pertussis toxin sensitives. However, it is not known whether, as is the case for NADPH oxidase’O, purinergic and pyrimidinergic activation of phos- pholipase C in these cells show differential pertussis toxin sen- sitivity.
In pertussis ~xin-in~nsitive signal transduction systems, the interaction of pyrimidinoceptors with G proteins will be more difficult to demonstrate; a pos- sible approach would be to test the sensitivity of agonist binding
q q El
The mechanism by which extra- cellular pyrimidine nucleotides regulate cell functions shows many properties characteristic of recep- tor-mediated processes. These in- clude stereospecificity for agonists, reversibility and desensitization of activation, involvement of G proteins, the generation of intra- cellular signal molecules and acti- vation of cellular effector systems.
There is substantial indirect evidence for the existence of pyrimidinoceptors distinct from purinoceptors.
Information so far available suggests that many cell types pos- sess pyrimidinoceptors and that these receptors are heterogeneous.
Figure 2 summarizes the mechan- isms involved in ?~id~e~ic activation of human myeloid cells.
HL-60 cells and human neutro- uhils are useful model svstems
‘to study the pyrimidinergi: regu- lation of cell functions. However, the physiological relevance of
TiPS - September 1989 [Vof. 101 pyrimidinergic regulation of cel- lular functions is as yet poorly undersrood, owing to the lack of information on how the release of pyrimidine nucleotides is con- trolled.
The development of potent and selective agonists and antagonists for pyrimidinoceptors is essential to characterize these receptors, and may provide a novel approach to intervene in various patho- logical states such as inflam- matory processes and vascular diseases.
Acknowkdgemenb
The authors are grateful to Mrs R. Kriiger for help in the prepar- ation of the manuscript. Work of the authors cited herein was sup- ported by grants of the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
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John S. Laze and Robert R. Bahnson
The poor therapeutic index and limited efficacy of current cancer chemother- ap~~c agents represent an ~mpo~ant pha~acolo~ca~ prab~m. Athough there has been a significant increase in our understandjng of the nnechanisms by which anticancer drugs kill mammalian cells, identification of new, effective anticancer agents during the last decade has been exceeding slow.
Thus, attention has focused on understanding the causes of drug resistance and on either sassing tumor cells to existing anticunc~ agents using what could be called ‘ckemoenhancers’, or protecting non-malignant tissues against serious untoward effects using ‘ckemoprotectors’. John Laze and Robert Bahnson review recent strategies attempting to modulate the activity of antineopiastic drugs.
When demand exceeds supply, people look for ways to increase the usefulness of the existing sup ply. So it currently is in cancer research: there are many malig- nancies that do not respond to chemotherapy and too few ex- citing novel drugs to test. This, combined with an elevated under- standing of the molecular basis of resistance to anticancer drugs, has kindled interest in identifying and developing pharmacological
f. S. Laze is Allegheny Foundation Professor and Ckairman of Pka~aco~gy and R. R.
Bahnson is ~s~fant Professor of Urologic Surgey at tke University of Pittsburgh School of Medicine, Pittsbugh, PA 15261, USA. Both authors are also members of the Pittsburgh Cancer Institute.
modulators of existing cancer chemotherapeutic agents to im- prove their therapeutic indices.
Two classes of modulator are being examined: chemoenhan- cers, which would sensitize tum- or cells; and chemoprotectors, which would selectively protect non-ma~~ant tissue.
To be a successful chemo- enhancer or chemoprotector, an agent must exhibit little toxicity itself; many such agents have no anticancer activity at all and some have other useful pharmacological properties. The clinically success- ful combination of methotrexate with leucovorin (folinate} pro- vides an important precedent for the chemoprotective approach;
cisplatin, currently one of the most popular anticancer drugs,
