ATP had been demonstrated for several, mainly inhibitory, effects on ..... giving 50% inhibition (ICs0) of diazepam binding is high, around 1. mM, but it has been ...
Bioscience Reports 2, 77-90 (1982) Printed in Great Britain
77
C e l l - m e m b r a n e receptors for purines Review T. W. STONE Department of Physiology, St. George's Hospital Medical School, University of London, London 574"17 ORE, U.K.
Purines are involved in many aspects of cell c h e m i s t r y - intermediary metabolism, nucleic acid synthesis, and the supply of highenergy phosphates to various active transport Systems. In addition, however, there appear to be specific receptor molecules located within the plasma membrane of some cell% which mediate changes of cell function in response to purines present in the extracellular fluid. It is t h e p u r p o s e of this r e v i e w to s u m m a r i z e the kind of functions subserved by those receptors as well as the basic structural requirements for their activation.
P h a r m a c o l o g i c a l Actions and the P l / P 2 Concept It has been recognized for several decades that the extracellular administration of some purines can have marked effects on the heart or visceral smooth muscle. These actions were discussed by Burnstock (1972) and f o r m a l i z e d into a concept of 'purinergic' neuronesneurones releasing a purine, probably adenosine triphosphate (ATP), as a neurotransmitter. This hypothesis arose partly to explain the responses of tissue to nerve stimulation which could not be accounted f o r by t h e i r c h o l i n e r g i c or adrenergic innervation. More recent reviews of peripheral purine pharmacology have appeared (Burnstock, 19gl; Baer & Drummond~ 1979)~ while Stone (1981a) has discussed in d e t a i l th e a c t i o n s and functions of purines with emphasis on the central nervous system. The f i r s t a t t e m p t to classify purine receptors was made by 5urnstock (1978) on the basis of inverted potency series and susceptibility to antagonism. Thus the order of potency adenosine > AMP > ATP had been demonstrated for several, mainly inhibitory, effects on smooth muscl% including the relaxation of vascular tissues, and these actions could be blocked by methylxanthines (caffei ne, theophylline, e t c . , ) in significantly lower concentrations than were needed to inhibit cyclic nucleotide phosphodiesterase. The recept or for these e f f e c t s was referred to as Pt (Burnstock, 1978). On the other hand, several excitatory effects of purines, notably on trachea, bladder, and parts of the intestine of some species are produced by ATP > ADP > AMP > adenosine and are not blocked by methylxanthines. This ATP receptor was dubbed P2" Although uinidine and 2-pyridylisatogen have been claimed by some authors Spedding et a l . 1975; Hunt et a l . 197g) to show antagonistic activity ~1982
The Biochemical Society
78
STONE
towards ATP, this view has not met an enthusiastic reception as both drugs are rather nonspecific in their effect s. (It is possible that the apparent nonspecificity in the action of quinidine could actually r e f l e c t blockade of engodenous ATP [see Stone, 19gla], but no hard evidence for this is yet available.) The PI/P2 classification is now frequently quoted in the pharmacol o g i c a l l i t e r a t u r e and used to draw a precise-sounding conclusion. Critics of the Pl / p2 concept assert that some numerical est i m at e of ranges of relative potency within the respective potency series should be a criterion of the classification. Such sceptics point to the case of several smooth muscles, where purine actions do not fit the above scheme (e.g. Clark et al., 1980; Baer & Frew, 1979)7 and indeed question the value of any specific nomenclature replacing the descriptive terms 'adenosine receptor' and 'ATP r e c e p t o r ' . As will be noted b elo w, this particular classification is of dubious value when considering some of the more subtle interactions of purines with other compounds. It is perhaps appropriate here to reinforce the idea that these r ecep to r s are accessible only to extracellularly located purines. The adenosine receptor, for example, can be activated by simple analogues which do not cross cell membranes, such as 2-chloroadenosine, as well as v e r y l a r g e m o l e c u l e s m a de by linking adenosine to a highmolecular-weight polymer (Olsson et al., 1976, 1977; Schrader et al., 1977). Evidence for the membrane location of the ATP r e c e p t o r is m o r e c i r c u m s t a n t i a l , but i n c l u d e s t h e e x t r e m e rapidity of ATP responses, as well as the high potencies of ATP analogues such as B , y - m e t h y l e n e ATP and a recently described series of diadenosine polyphosphates (Stone, 19glb, 1982; Stone & Perkins, 1981) which are m e t a b o l i z e d r e l a t i v e l y slowly, and which p e n e t r a t e into cells very poorly, if at all.
Mechanisms
of Action
Little is known about the mechanism of responses mediated by the ATP receptor. A limited amount of evidence from smooth-muscle electrophysiology suggests activation of a potassium channel (T om i t a & Watanabe, 1963; Burnstock, 1972; Hartzell, 1979), an action which also seems to occur in isolated hepatocytes (Burgess et al., 1979) and even HeLa ceils (Alton & Lamb, 1980). An increase of calcium influx has also been noted in the presence of ATP (Goto et al., 1977, 1978; Ribeiro, 1979), and such an e f f e c t might well underlie some cont r a c t i l e e f f e c t s of ATP. Activation of the adenosine receptor has received more attention than that of the ATP receptor, possibly because the form er entrains a g r e a t e r v a r i e t y of c e l l u l a r responses and because it is of more obviously direct practical value. Thus, while the signilicance of the ATP r e c e p t o r remains obscure, the adenosine recept or is now widely a c c e p t e d as having a major physiological role, for example, in the control of vascular tone (Berne et al., 1979). The main consequence of adenosine recept or activation seems to be a r e d u c t i o n in t h e a v a i l a b i l i t y of calcium ions. This has been demonstrated most clearly by direct studies of #5Ca2+ uptake i n t o
PURINE
RECEPTORS
79
cerebral synaptosomes (Ribeiro et al., 1979) as well as by electrophysiological studies of the cardiac action potential (Goto et al., 197g; Schrader et al., 1975, 1979) and studies of the calcium dependence of adenosine responses (Hayashi et al., 1981; Kuroda et al., I976b). When acting on nerve terminals, this effect of adenosine results in a marked inhibition of neurotransmitter release, a phenomenon which has been observed on somatic (Ginsborg & Hirst, 1972; Ribeiro & Walker, 1975) and visceral autonomic nerves (Clanachan et al., 1977; Enero & Saidman, 1977; Gustaffson et al., 1978; Hedqvist & Fredholm, 1979; Ribeiro, ]979; Su, 1978; Verhaege et al., 1977; Vizi & Knoll, ]976), as well as in the central nervous system (CNS) (Harms et al., ]978, 1979; Hollins & Stone, 1980). The depressant effects of adenosine on neuronal firing rate in the CNS are blocked by methylxanthines and may involve some reduction of excitatory transmitter release (Phillis & Kostopoulos, 1975; Perkins & Stone, ]980). It is also clear, however, that as well as pre-synaptic inhibitory a c t i o n s , adenosine has a c t i o n s at p o s t - j u n c t i o n a l sites. Hence adenosine causes a relaxation of vascular muscle even in the absence oL a tonic c o n s t r i c t o r innervation (Mustafa, 19g0). L u c h e l l i f o r t i s et ai. ( [ 9 8 1 ) have also r e c e n t l y described a post-junctional inhibitory a c t i o n on the cat n i c t i t a t i n g m e m b r a n e , a p r e p a r a t i o n which is one of only a small number which seem to lack adenosine r e c e p t o r s on the pre-synaptic nerve terminals~ But adenosine does not have only inhibitory e f f e c t s on smooth muscle. On the guinea-pig t r a c h e a , for e x a m p l e , adenosine causes a c o n t r a c t i o n of the muscle, and, unusually, it is roughly e q u i p o t e n t with ATP in this r e s p e c t . As stable analogues of ATP have l i t t l e e f f e c t on this tissue, Christie and S a t c h e l l ( ] 9 8 0 ) have proposed that both adenosine and ATP are acting on an adenosine receptor. One problem with this view is t h a t whereas an i n c r e a s e of calcium influx, which could explain muscular c o n t r a c t i o n , has been found in response to ATP in some tissues ( G o t o et al., 1977, 197g; R i b e i r o e t al., 1 9 7 9 ) , t h i s e f f e c t does not seem to have been d e m o n s t r a t e d in response to adenosine. Adenosine p h a r m a c o l o g y and r e c e p t o r classification b e c o m e s even more confusing when i n t e r a c t i o n s with o t h e r compounds are considered. The early biochemical observations of S a t t i n and Rail (1970) which will be discussed below included the observation t h a t adenosine (>ATP) and n o r a d r e n a l i n e exhibited a mutually p o t e n t i a t i v e i n t e r a c t i o n on the a c t i v a t i o n of a d e n y l a t e cyclase in brain slices ( S a t t i n & Rail, 1970; S a t t i n et al., 1975; Daly, 1976). A p o t e n t i a t i o n b e t w e e n adenosine and n o r a d r e n a l i n e could be d e m o n s t r a t e d e l e c t r o p h y s i o l o g i c a l l y but was of much smaller m a g n i t u d e (Stone & Taylor, 1978). Hedqvist and F r e d h o l m ( ] 9 7 6 ) r e p o r t e d most c l e a r l y on the distinction b e t w e e n the pre-synaptic i n h i b i t o r y p r o p e r t i e s of adenosine and its ability to e n h a n c e t h e e f f e c t s of n o r a d r e n a l i n e p o s t - s y n a p t i c a l l y . The postsynaptic interaction s e e m s to be r e s t r i c t e d to c~l_adrenoreceptor s ( H e d q v i s t & F r e d h o l m , 1976; Sattin & Rail, 1970; Jones, I981), the a b s e n c e of a n y i n t e r a c t i o n in guinea-pig c e r e b e l l u m , for example, p r e s u m a b l y r e f l e c t i n g the p r e s e n c e here only of B - a d r e n o r e c e p t o r s . A similar potentiative p h e n o m e n o n has been d e m o n s t r a t e d on isolated vascular muscle and on the guinea-pig vas d e f e r e n s (Holck & Marks, 1978). This means, of course, t h a t on Some tissues, most
80
STONE
notably on vascular muscle, adenosine can have a direct action to cause relaxation and an indirect action to reduce noradrenaline release, as well as causing a potentiation of the post-junctional c o n t r a c t i l e e f f e c t of noradrenaline. Clearly the system must normally function as a d e l i c a t e l y b a l a n c e d e q u i l i b r i u m , and conceivably only a small displacement of that equilibrium might be sufficient to trigger the changes that lead to chronic hypertension (Kamikawa et al., 1980). It is t h e r e f o r e especially exciting that one of the common antihypertensive drugs, hydrallazine, has recently been shown to act at a purine r e c e p t o r site in so far as its muscle relaxant activity can be reversed o r prevented by ATP (Chevillard et al., 1981).
Receptor Sensitivity There are two further interesXing f a c e t s of this p u r i n e noradrenaline interaction. One is that it may be partly related to the functional s t at e of the relevant receptor. Holck and Marks (1978), for example, noted that not only did adenosine increase responses to noradrenaline, but if the tissue was densensitized to the amine by applying high concentrations into t h e b a t h , then adenosine hastened the r e c o v e r y of responsiveness, i.e. resensitization. The order of potency of p u r i n e s was di f f er e nt for the two actions. ATP for example r e d u c e d r a t h e r than increased noradrenaline responses, and had no e f f e c t on the rate of s - r e c e p t o r resensitization. What makes this phenomenon particularly interesting is that similar observations have been made on acetylcholine receptors. As long ago as 19it4, Buchthal and Kahlson reported on the increased response to acetylcholine produced by ATP at the neuromuscular junction. As these experiments were performed in vivo, it is possible that local changes of blood flow were at least partly responsible for this e f f e c t . H o w e v e r , Ewald ( 1 9 7 6 a , b ) , r e i n v e s t i g a t i n g t h e i n t e r a c t i o n with intracellular electrophysiological methods, came to essentially similar conclusions. The similarity between the calcium dependence of the potentiation and that of the normal acetylcholine recept or interaction led Ewald ( 1 9 7 6 a , b ) to s u g g e s t t h a t ATP m i g h t f a c i l i t a t e the transmitter-receptor interaction. ATP also reduced the rat e of end-plate desensitization to acetylcholine. Most recently, however, Akasu et al. (1981), using the voltage-clamp technique, have shown that ATP does not alter the affinity of acetylcholine for its receptor, and have concluded that the enhancement of acetylcholine sensitivity r e s u l t s f r o m e i t h e r an increase in the conductance of unit ionic channels or of the number of available channels, i.e. at a site distal to the r ecept or molecule. S e v e r a l Russian authors have come to the conclusion that the presence of ATP can regulate the sensitivity of cholinoreceptors in the h e a r t ( S a k h a r o v & T u r p a e v , 1968; T u r p a e v & S a k h a r o v , 1973; Nistratova, 1968). These observations raise again the proposal of Stone (1978) that one of the main physiological functions of endogenous purines may be the regulation of the activity of tissue by changing the balance between, say, receptors for catecholamines and a c e t y l c h o l i n e , or between muscarinic and nicotinic receptors. An increase in the local concentration of ATP, for example, would lead to
PURINE
RECEPTORS
81
an increased sensitivity to acetylcholine but a decreased sensitivity to noradrenaline. Adenosine on the other hand would tend to increase a - a d r e n o r e c e p t o r sensitivity but does not seem to a f f e c t cholinoceptor sensitivity (Akasu et al., 1981).
Relationship to Cyclic-AMP-Generating Systems T h e s e c o n d reason ior the particular interest in the functional post-junctional potentiation between adenosine and noradrenaline is that j u s t - s u c h a potentiation was among the first observations made by Sattin and Rail (1970) in the study which demonstrated for the first t i m e t h a t a d e n o s i n e was able to a c t i v a t e cyclic-AMP-generating systems in slices of guinea-pig cerebral cortex. It was later found th at the failure of noradrenaline to cause an increased concentration oi cyclic AMP on second or subsequent application could be prevented by the inclusion of adenosine (Schultz & Daly, 1973). This sounds highly reminiscent of the f a c i l i t a t e d resensitization of smooth muscle discussed above. This then raises the question of the relationship between the functional e f f e c t s of purines and their interactions with n eu r o tr an s m i t t er s , and the activation of adenylate cyclase. E x p e r i m e n t s by K u r o d a et al. ( 1 9 7 6 a ) showing a correlation between the ext ent and time course of changes of cyclic AMP levels and the depression by adenosine of synaptically evoked potentials in the guinea-pig ol f a c t or y slice are still to be found quoted as support for a positive relationship between these parameters. However, later work by the same group, in which a b e t t e r time resolution of the b i o c h e m i c a l results was achieved, clearly showed that the el ect rophysiological changes occUrred well b e f o r e the cyclic AMP changes (Kuroda, 197g). Other groups have ats0 concluded that adenylate cyclase activation is not necessary for functional changes to occur (Smellie et al,, 1979; Okada & Saito, 1979; Scholfield, 197g; Reddington & Schubert, 1979; Dunwiddie & H ol l e r , 19g0) and it has been noted earlier that the s mall d e g r e e of p o t e n t i a t i o n between adenosine and noradrenaline o b s e r v e d e l e c t r o p h y s i o l o g i c a l l y ( S t o n e & Taylor, 197g) would be difficult to reconcile with the large potentiation Seen on cyclic AMP levels (Sattin et al., 1975). It would seem, then, that the receptors for adenosine's functional e f f e c t s , such as inhibition of t r a n s m i t t e r release, and elevation of cyclic AMP levels must be distinct entities. The two receptors are clearly very similar as they exhibit a similar relative p r e f e r e n c e for a number of adenosine derivatives, and both are blocked by similar concentrations of methylxanthines. Part of the reason for the differences between the two sites could, of course, be m o r p h o l o g i c a l , t h e c y c l i c - A M P - e l e v a t i n g s i t e s being in general post-synaptic and those inhibiting t r a n s m i t t e r release being pre-synaptic (E)eMey et al., 1979). However, some clear pharmacological diff e r e n c e s bet w e e n these sites do exist, such as the fact that the L-isomer of phenylisopropyladenosine is 100-fold more potent than the D-isomer in causing a reduction of post-synaptic potentials, whereas it is only #- to 5-fold more potent in elevating cerebral cyclic AMP levels (Smellie et al., 1979). The two receptor sites involved, of course, would both belong to the Pt category.
82
STONE
Receptors Modulating Adenylate Cyclase Activity Londos and Wolff (1977) drew attention to the fact that in some tissues adenosine increased cyclic AMP levels while in others there was a decrease. By examining a series of adenosine analogues these authors were able to conclude that at least two separate purine receptors existed exhibiting different structural spec}ficities. The 'R' site required an intact ribose portion of the molecule and mediated an increase of adenylate cyclase activity. The 'P' site showed little tolerance to modification of the purine ring but was relatively unaffected by changes of the ribose portion, 2'5'-dideoxyadenosine being a good agonist. Activation induced decreases of cyclase activity. A further important difference between these sites was the conclusion that the 'P' site was only accessible to compounds after they penetrated into the cytoplasm and t h i s property presumably accounted in part for the resistance of t h i s site to blockade by methylxanthines. Shortly after these experiments, Van Calker et al. (1979) reported on a subdivision of the 'R' site. As in the case of the original 'R' site, the receptors described by Van Calker et al. (1979) were considered to be extracellularly directed, as inhibition of adenosine uptake did not diminish the responses. Their subdivision was made partly on the basis of concentration-dependent responses to adenosine and partly on the basis of inverted potency series. Thus their Al site was s t i m u l a t e d p r e f e r e n t i a l l y b y N6-phenylisopropyladenosine, whereas t h e A 2 site was a c t i v a t e d more by adenosine itself. The A I r e c e p t o r inhibited the accumulation of c y c l i c AMP w h e r e a s the A 2 site provoked an increase of cyclic AMP levels. Both sites, of course, w e r e blocked by m e t h y l x a n t h i n e s . The most r e c e n t c h a p t e r in this sequence is the r e p o r t by Londos e t al. (1980) of a subdivision of the 'R' site into R a and R i sites. H o w e v e r , these r e c e p t o r s show e x a c t l y the same p r o p e r t i e s as Van C a l k e r ' s A 1 and A2, viz., r e q u i r e m e n t for an i n t a c t ribose moiety, block by m e t h y l x a n t h i n e s , e x t e r n a l location, phenylisopropyladenosine > adenosine causes inhibition of c y c l i c AMP a c c u m u l a t i o n at the R i site, but adenosine > phenylisopropyladenosine a c t i v a t e s a d e n y l a t e c y c l a s e at t h e R a site. An additional finding c o n t r i b u t e d by Londos et al. (1980) was that 5'-/V-ethylcarboxamide adenosine (ECA) was more p o t e n t than adenosine and phenylisopropyladenosine at R a whereas it was w e a k e r than e i t h e r of these at R i. T h e v a r i o u s s c h e m e s of r e c e p t o r classification have been summ a r i z e d in Table l, and Table 2 is an a t t e m p t to r a t i o n a l i z e these w h e r e s u f f i c i e n t l y close r e c e p t o r similarities have been d e m o n s t r a t e d . It should be s t a t e d again, however, t h a t a number of p r e p a r a t i o n s or tissues show purine responses which do not p e r m i t easy classification into any of the c a t e g o r i e s of T a b l e 1. A b e t t e r a p p r e c i a t i o n of the similarities or v a r i e t y of r e c e p t o r s ideally needs the testing of a large series of compounds, the investigations of Bruns (1980a,b,c) in which up to 128 analogues were e x a m i n e d being e x e m p l a r y in this r e s p e c t . As the number of p o s t u l a t e d r e c e p t o r sites increases it also has to be c o n s i d e r e d t h a t some subtle d i f f e r e n c e s of a p p a r e n t r e c e p t o r v a r i e t i e s m a y result m e r e l y from the d i f f e r e n t proteo-lipid e n v i r o n m e n t s existing in the cell walls of d i f f e r e n t tissues (Stone, 197#).
PURINE
RECEPTORS
83
r.--
,--
g
o".
u++4 ,._.4 3:
g o
g
o
? m
~
~g
0 r
,., ,.,
"~ .~.-+ +
+: i+ m +.,.4
o
," +:,.,,.-., =+ ,.+ += ~
+.-, &
-'r.
tll ,.,..+ 0
~3
II
4..+
II
rl
+L + oo . ~ xr
++
g
.,.4 0 . ,..,+
,~,~. +
,"4 .,4
+J +,..l
..,.,+
%
?
t-I
I o ,-1
e~ .
"0 9 ~
.I 0 ~ ,.~ .,-I
On 0",
J
g
~c
c
c~
co c~ o
A 0.0 C 9N
C~
~ m
9
I--I C
"0
I
I
.,-I &J
c C
u~
0 C
0
I 0
I 0
0
0
I Og
C
I
E~
0 C
C
C 0
~C 0
~ C
0
u~
C
I I
I
C
C
I r--m
~>~0 0
C~
I
~;
!
!
'0
CO ,-~
l
I
u~ ~ ~J M 0 0
I
C ~
~
0 0
~
~
0
&J
bid
.,.4 ~J 0
C ~ 0 4J ,.4
~
~aO 0
0
PURINE
RECEPTORS
87
labelled. The more recent arrival of labelled adenosine analogues which promise to be more specific for a particular receptor population (such as N6-cyclohexyl-adenosine and 173-diethyl-g-phenylxanthine) should help to clarify the properties o1: individual binding sites. F u t u r e Trends Probably the main goal of much purine r e s e a r c h within the next f e w y e a r s will be to c o r r e l a t e the r e c e p t o r types d e m o n s t r a t e d b i o c h e m i c a l l y with those observed physiologically, and to c o r r e l a t e e i t h e r with a p p r o p r i a t e binding studies. A s t a r t in this direction has been evident from the publications of Smellie et al. (1979) and of P a t o n (19gi)7 who have shown the much greater a c t i v i t y of L-phenylisopropyladenosine with r e s p e c t to the D - i s o m e r when p r o d u c i n g inhibition of t r a n s m i t t e r r e l e a s e in the c e n t r a l and peripheral nervous systems r e s p e c t i v e l y . This p o t e n c y d i f f e r e n c e .is c h a r a c t e r i s t i c of the A t or R i site ( T a b l e [) and implies a physiological as well as a biochemical r e l e v a n c e o1: this r e c e p t o r . In s u m m a r y , it m a y be e m p h a s i z e d again t h a t the actions of purines on cells discussed in this review are m e d i a t e d by purines in the e x t r a c e l l u l a r space acting on r e c e p t o r s in the cell m e m b r a n e . Several means o1: classifying those r e c e p t o r s have been described and are s u m m a r i z e d in Table 1. While it remains an open question as to whether any of the proposed schemes have any real r e l e v a n c e or relationship to the actions of endogenous purines, the e x i s t e n c e of multiple r e c e p t o r s of one type or a n o t h e r must be considered established. This in turn implies an i m p o r t a n t , well-developed 7 and highly c o m p l e x web of functions for purines outside the cell wall c o m p l e menting and i n t e r a c t i n g with the v a r i e t y o1: functions r e c o g n i z e d inside the cell.
Relerences Aiton JF & Lamb JF (1980) Quart. J. Exp. Physiol. 65, 47-62. Akasu T, Hirai K & Koketsu K (1981) Br. J. Pharmacol. 74, 505-507. Baer HP & Drummond GI (1979) Physiological and Regulatory Functions of Adenosine and Adenine Nucleotides, Raven Press7 New York. Baer HP & Frew R (1979) Br. J. Pharmacol. 67, 293-300. Berne RM, Foley DH7 Watkinson WP, Miller WL, Winn HR & Rubio R (1979) in Physiological and Regulatory Functions of Adenosine and Adenine Nucleotides (Baer HP & Drummond GI, eds), pp 117-1267 Raven Press, New York. Blume AJ & Foster CJ (1976) J. Biol. Chem. 251, 3399-3404. Bruns RF (1980a) Canad. J. Physiol. Pharmacol. 58, 673-691. Bruns RF (1980b) Biochem. Pharmacol. 30, 325-332. Bruns RF (1980c) Arch. Phamacol. 315, 5-13. Bruns RF, Daly JW & Snyder SH (1980) Proc. Natl. Aead. Sci. U.S.A. 77, 5547-5551. Buchthal F & Kahlson G (1944) Nature 1547 178-179. Burgess GM, Claret M & Jenkinson DH (1979) Nature 279, 544-546.
88
STONE
Burnstock G (1972) Pharmacol. Revs. 24, 509-581. Burnstock G (1978) in Cell Membrane Receptors for Drugs and Hormones (Straub RW & B o l i s L, eds), pp 107-118, Raven Press, Hew York. Burnstock G (1981) J. Physiol. 313, 1-35. Chevillard C, Saiag B & Worcel M (1981) Br. J. Pharmacol. 73, 811-818. Christie J & Satchell DG (1980) Br. J. Pharmacol. 70~ 512-514. Clanachan AS, Johns A & Paton DM (1977) Neuroscience 2, 597-602. Clark LA, Small RC & Turnbull MJ (1980) Br. J. Pharmacol. 69, 331-332. Daly JW (1976) Life Sci. 18, 1349-1358. Davies LP, Cook AF, Poonian M & Taylor KM (1980) Life Sci. 26~ 1089-1098. DeMey J, Burnstock G & Vanhoutte PM (1979) Europ. J. Pharmacol. 55~ 401-406. Dunwiddie TV & Hoffer BJ (1980) Br. J. Pharmacol. 69, 59-68. Durra P & Mustafa SJ (1979) J. Pharmacol. Exp. Therap. 211, 496501. Dutta P & Mustafa SJ (1980) J. Pharmacol. Exp. Therap. 214, 496-502. Enero MA & Saidman BQ (1977) Arch. Pharmacol. 297, 39-46. Ewald DA (1976a) J. Membr. Biol. 297 47-65. Ewald DA (1976b) J. Membr. Biol. 29, 67-79. Fain JN & Malbon CC (1979) Mol. Cell. Biochem. 25~ 143-169. Ginsborg BL & Hirst GDS (1972) J. Physiol. 224, 629-645. Goto M, Yatani A & Tsuda Y (1977) Japan. J. Physiol. 27, 81-94. Goto M 7 Yatani A & Tsuda Y (1978) Japan. J. Physiol. 28~ 611625. Guroff G, Dickens G, End D & Londos C (1981) J. Neurochem. 37, 1431-1439. Gustaffson L, Hedqvist P, Fredholm BB & Lundgren G (1978) Acta Physiol. Scand. 104, 469-478. Harms HH, Wardeh G & Mulder AH (1978) Europ. J. Pharmacol. 49, 305-308. Harms HH, Wardeh G & Mulder AH (1979) Neuropharmacol. 18~ 577-580. Hartzell HC (1979) J. Physiol. 293, 23-50. Hayashi E, Yamada S & Shinozuka K (1981) Japan. J. Pharmacol. 31, 141-143. Hadqvist P & Fredholm BB (1976) Arch. Pharmacol. 293, 217-224. Hedqvist P & Fredholm BB (1979) Acta Physiol. Scand. 1057 120-122. Henderson JF (1980) Pharmacol. Therap. 8, 605-627. Henderson JF & Scott FW (1980) Pharmacol. Therap. 8, 539-571. Holck MI & Marks BH (1978) J. Pharmacol. Exp. Therap. 2057 104117. Hollins C & Stone TW (1980) Br. J. Pharmacol. 69, 107-112. Hunt WB, Parsons DG, Wahid A & Wilkinson J (1978) Br. J. Pharmacol. 63, 378-379. Jones DJ (1981) J. Pharmacol. Exp. Therap. 219, 370-376. Kamikawa Y, Cline WH & Su C (1980) Europ. J. Pharmacol. 66, 347-354.
PURINE
RECEPTORS
89
Kuroda Y, Saito M & Kobayashi K (1976a) Brain Research 109, 196201. Kuroda Y, Saito M & Kobayashi K (1976b) Proc. Japan. Acad. 52, 86-89. Kuroda Y (1978) J. Physiol. (Paris) 74, 463-470. Levinson SL & Blume AJ (1977) J. Biol. Chem. 252, 3766-3774. Londos C & Wolff J (1977) Proc. Natl. Acad. Sci. U.S.A. 74, 54825486. Londos C, Cooper DMF & Wolff J (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 2551-2554. Luchellifortis MA, Fredholm BB & Langer SZ (1981) J. Pharmacol. Exp. Therap. 219, 235-242. Malbon CC, Hert RC & Fain JN (1978) J. Biol. Chem. 253, 31143122. Marangos PJ, Paul SM, Parma AM, Goodwin FK, Syapin P & Skolnick P (1979a) Life Sci. 24, 851-858. Marangos PJ, Paul SM, Goodwin FK & Skolnick P (1979b) Life Sci. 25, 1093-1102. McIlwain H (1972) Biochem. Soc. Symp. 36, 69-85. Mustafa SJ (1980) Mol. Cell. Biochem. 31, 67-87. Newman ME, Patel J & McIlwain H (1981) Biochem. J. 194, 611-620. Nistratova SN (1969) in Neurobiology of Invertebrates (Salanki J, ed), pp 315-326, Plenum Press, New York. Okada Y & Saito M (1979) Brain Research 160, 369-371. Olsson RA, Davis CJ, Khouri EM & Patterson RE (1976) Circ. Res. 39, 93-98. Olsson RA, Davis CC & Khouri EM (1977) Life Sci. 21, 1343-1350. Paton DM (1981) J. Auton. Pharmacol. 1, 287-290. Perkins MN & Stone TW (1980) Arch. Int. Pharmacodyn. 246, 205-214. Phillis JW & Kostopoulos GK (1975) Life Sci. 17, 1085-1094. Phillis JW, Wu PH & Bender AS (1981) Gen. Pharmacol. 12, 6770. Reddington M & Schubert P (1979) Neurosci. Lett. 14, 37-42. Ribeiro JA (1979) J. Theor. Biol. 80, 259-270. Ribeiro JA & Walker J (1975) Br. J. Pharmacol. 54, 213-218. Ribeiro JA, Sa-Almeida AM & Namorado JM (1979) Biochem. Pharmacol. 28, 1297-1300. Sa|~arov DA & Turpaev TM (1968) in Neurobiology of Invertebrates (Salanki J, ed), pp 305-314, Plenum Press, New York. Sattin A & Rall TW (1970) Molec. Pharmacol. 6, 13-23. Sattin A, Rall TW & Zanella J (1975) J. Pharmacol. Exp. Therap. 192, 22-32. Scholfield CN (1978) Br. J. Pharmacol. 63, 239-244. Schrader J, Rubio R & Berne RM (1975) Mol. Cell. Cardiol. 7, 427433. Schrader J, Nees S & Gerlach E (1977) Pflug. Arch. Ges. Physiol. 369, 251-257. Schrader J, Gerlach E & Baumann G (1979) in Physiological and Regulatory Functions of Adenosine and Adenine Nucleotides (Baer HP & Drummond G, eds), pp 137-144, Raven Press, New York. Schultz J & Daly JW (1973) J. Biol. Chem. 248, 843-852.
90
STONE
Schwabe U~ Kiffe H, Puchstein C & Trost T (1979) Arch. Pharmacol. 310, 59-68. Schwartz AL, Stern RC & Polmar SH (1978) Clin. Immunol. Immunopathol. 9, 479-505. Smellie FW, Daly JW, Dunwiddie TV & Hoffer BJ (1979) Life Sci. 257 1739-1748. Spedding M~ Sweetman AJ & Weetman DF (1975) Br. J. Pharmacol. 53~ 575-583. Stone TW (1974) Arch. Int. Pharmacodyn. 2107 365-373. Stone TW (1978) Biochem. Soc. Trans. 6, 858-862. Stone TW (1981a) Neuroscience 6, 523-555. Stone TW (1981b) Europ. J. Pharmacol. 75, 93-102. Stone TW (1982) in Physiology and Pharmacology of Adenine Derivatives (Kuroda Y7 Phillis JW & Daly JW~ eds), Raven Press~ New York (in press). Stone TW & Perkins MN (1981) Brain Research 2297 241-245. Stone TW & Taylor DA (1978) Brain Research 147~ 396-400. Su C (1978) J. Pharmacol. Exp. Therap. 204~ 351-361. Tallman JF, Paul SM, Skolnick P & Gallagher DW (1980) Science 207, 274-281. Tomita T & Watanabe H (1963) J. Physiol. 231~ 167-178. Turpaev TM & Sakharov DA (1973) in Comparative Physiology, vol ] (Michelson M J, ed), pp 345-355, Pergamon Press, London. Van Calker D, Muller M & Hamprecht B (1979) J. Neurochem. 337 999-1005. Verhaege RH~ Vanhoutte PM & Shepherd JT (1977) Circ. Res. 40, 208-215. Vizi ES & Knoll J (1976) Neuroscience I, 391-398. Williams M & Risley EA (1980) Proc. Natl. Acad. Sci. U.S.A. 77, 6892-6896. Wu PH7 Phillis JW~ Balls K & Rinaldi B (1980) Canad. J. Physiol. Pharmacol. 58~ 576-578. Wu PH, Phillis JW & Bender AS (1981) Life Sci. 28, 1023-1031.
