- Email: [email protected]
Will the true receptor affinity please step forward
TiPS - February 2989 lVol. 101 tion? Coarcted dogs in which the adrenal medulla had been previously denervated show, of course, no increase in plasma epinephrine levels. They also do not develop cardiac hypertrophy”, leading the authors to suggest that epinephrine was a trophic factor for the heart. It is clear many problems remain to be investigated in the pharmacology of these related catecholamines. In our present state of incomplete knowledge, it appears that there is a degree of redundancy in stress responses. This makes good evolutionary sense, in that redundant systems are stable systems. It is reassuring to know you have a handbrake to use in the unlikely event your brake fluid leaks away. But this appearance of redundancy may only mask ignorance. A closer understanding of adrenomedullary and sympathetic interactions may indicate that each has clear but integrated responsibilities. B. MAX
References 1 Cleffmann, G. (1964) Exp. CelL Res. 35,
590 600 2 Haluri~, K. M. and Ohkawara, A. (1967) in . Advnnces irz Biology of Skin (Montagna, W. and Ho, F., eds), pp. 241-251, Pergamon Press 3 Baker, J. T. (1974) Et~denuour33, 11-17 4 Fisher, L. A. et nl. (1983) Nature 3C.3, 534-536 5 Brown, M. R. and Fisher, L. A. (2384) 1. Am. Med. Assoc. 251, 1310-1315 6 Best, J. D. and Halter, J. B. (1982: 1. C/in. Emfocrinol. Met&. 55, 263-268 7 Axelrod, J. (1962) /. Biol. Clzetn. 237, 1657-1660 8 Gerich, J. ef al. (1979) Am. 1. Pkysiol. 236, E380-E385 9 Gillis, C. N. and Roth, J. A. (1976) Biochent. Phnrmncol. 25, 2547-2553 10 Sudo, A. (1987) Life Sci. 41, 2477-2484 11 Clutter, W. E., Bier, 0. M., Shah, S. D. and Cryer, P. E. (1980) J. Clip. Inrrest.66, 94-101 12 Esler, M. et al. (1984) 1. Autos. New. Syst. 11, 125-144 13 Zeigler, M. G., Lake, C. R., Wood, J. H., Brook, B. R. and Ebert, H. (1977) 1. Netrrocke?n.28. 677-679 14 &own. M. J., Allison, D. J., Jenner, D. A., Lewis, P. J. and Dollery, C. T. (1981) Lmcet i, 174-177 15 Esler; M., Leonard, I’., O’Dea, K., Jackman, G., Jennings, G. and Korner, P. (1982) /. Cmfiounsc. Plrnmn~of. 4,5152 16 Hjemdahl, P. (1987) Life Sci. 41,841-844 17 Silverberg, A. 5.. Shah, S. D., Haymond, M. W. and Cryer, I’. E. (1978) Am. J. Physiol. 234, E252-E256 18 Womble, I. ‘Y, Haddox, M. K. and Russell, 6. I!. (1978) Life Sci. 23, 1951-1958 19 Womble, J. R., Larson, D. F., Copeland, J. G., Brown, B. R., Haddox, M. K. and Russell, D. H. (1980) Life Sci. 27, 2417-2420
63
Is affinity an adequate basis for receptor chssificaticm?
Will the true receptor affinity please step _ forward In a recent letter, Mackay (TiPS, May 1988)’ commented on our observation2r3 that there seems to be a continuous variation in apparent agonist affinity of norepinephrine for the cul-adrenoceptor. We surmised that this might be due, at least in part, to local cellular influence(s). Mackay suggested that if the ternary complex model of drug action is applicable, then the important cellular influ. ence on affinity might be the local concentration of effector molecules. According to the simplified ternary complex model, the apparent affinity constant &(app) of an agonist A for its receptor is: &(aPP)
=
KIA
+
&A
&A
XT
(1)
where KIA is the receptor constant, KZA is the affinity constant of the RA complex for effector molecule X and XT is the local tissue concentration of the effector molecule. This relationship has recently been further elaborated by Morgan et al4 who pointed out that, with further assumptions, [RAXI could be considered the operational determinant of tissue response. Effector molecule concentration, however, is not the only possible local cellular parameter to influence receptor affinity. For example, it is well known that certain intracellular factors such as ions and possibly the phospholipid content of the membrane microenvironment can regulate affinity5, yet these p;i;:neters do not form part of the proposed ternary complex. In fact K~A, the true receptor affinity, simple as this might be in concept, probably cannot be accurately determined at the moment because the receptor can only be adequately assessed under experimental circumstances that might influence this measurement, for example in a phospholipid or detergent environment. It is known that the receptor is associated with molecuies, e.g. phospholipids, that probably influence the three-dimensional
shape of the agonist recognition site. Thus, Eqn 1 may lack an important element, specifically the environmental influence on the receptor, the receptor-effector complex, or both. Agonist &(app) for the 01~adrenoceptor varies not only between the same tissue in different locations in the same species, but between the same tissue in different species, in the same tissue during maturation, between different individuals of the same species, as the result of disease and with the technique used to prepare tissues for affinity determination. In addition, there is increasing evidence for variation of the affinity of antagonists for the cul-adrenoceptors’. In the face of such diversity of one of the essential characteristics that determine receptor-mediated response, it might well be asked how a satisfactory comprehensive classification can be receptor achieved. It might be that an approach completely different from that presently employed will be necessary. A receptor might have to be described by an affinity profile determined under prescribed circumstances-an affinity profile to key ligands. The true affinity of a receptor molecule is an important chemical feature; however, the affinity of the receptor in situ, the K*(app) is the important functional element. JOHN AND
S.
MARTIN
A.
BEVAN
SHREEVE
Depnrfmentof Pharmncology, University Vermont, Bzrlilrgforz,VT 05405, USA.
References 1 Mackay, D. (1988) Trends 2 3 4 5
Ph~rmacol.
of
Sci.
9, 156-157 Bevan, J. A., Bevan, R. D., Kite, K. and Oriowo, M. A. (1988) Trends PharmacoL Sci. 9, 87-89 Bevan, J. A., Oriowo, M. A. and Bevan, R. D. (1986) Science 234, 196-197 Morgan, P. H., Lutz. M. W. and Kenakin. T. P. (19881 Tretzds Phnmmcol. Sri. 9, 551-352 ’ Bevan, J A., Bevan, R. D. and Shreeve, S. M. FASEB I. (in press)
References 1 Cleffmann, G. (1964) Exp. CelL Res. 35,
590 600 2 Haluri~, K. M. and Ohkawara, A. (1967) in . Advnnces irz Biology of Skin (Montagna, W. and Ho, F., eds), pp. 241-251, Pergamon Press 3 Baker, J. T. (1974) Et~denuour33, 11-17 4 Fisher, L. A. et nl. (1983) Nature 3C.3, 534-536 5 Brown, M. R. and Fisher, L. A. (2384) 1. Am. Med. Assoc. 251, 1310-1315 6 Best, J. D. and Halter, J. B. (1982: 1. C/in. Emfocrinol. Met&. 55, 263-268 7 Axelrod, J. (1962) /. Biol. Clzetn. 237, 1657-1660 8 Gerich, J. ef al. (1979) Am. 1. Pkysiol. 236, E380-E385 9 Gillis, C. N. and Roth, J. A. (1976) Biochent. Phnrmncol. 25, 2547-2553 10 Sudo, A. (1987) Life Sci. 41, 2477-2484 11 Clutter, W. E., Bier, 0. M., Shah, S. D. and Cryer, P. E. (1980) J. Clip. Inrrest.66, 94-101 12 Esler, M. et al. (1984) 1. Autos. New. Syst. 11, 125-144 13 Zeigler, M. G., Lake, C. R., Wood, J. H., Brook, B. R. and Ebert, H. (1977) 1. Netrrocke?n.28. 677-679 14 &own. M. J., Allison, D. J., Jenner, D. A., Lewis, P. J. and Dollery, C. T. (1981) Lmcet i, 174-177 15 Esler; M., Leonard, I’., O’Dea, K., Jackman, G., Jennings, G. and Korner, P. (1982) /. Cmfiounsc. Plrnmn~of. 4,5152 16 Hjemdahl, P. (1987) Life Sci. 41,841-844 17 Silverberg, A. 5.. Shah, S. D., Haymond, M. W. and Cryer, I’. E. (1978) Am. J. Physiol. 234, E252-E256 18 Womble, I. ‘Y, Haddox, M. K. and Russell, 6. I!. (1978) Life Sci. 23, 1951-1958 19 Womble, J. R., Larson, D. F., Copeland, J. G., Brown, B. R., Haddox, M. K. and Russell, D. H. (1980) Life Sci. 27, 2417-2420
63
Is affinity an adequate basis for receptor chssificaticm?
Will the true receptor affinity please step _ forward In a recent letter, Mackay (TiPS, May 1988)’ commented on our observation2r3 that there seems to be a continuous variation in apparent agonist affinity of norepinephrine for the cul-adrenoceptor. We surmised that this might be due, at least in part, to local cellular influence(s). Mackay suggested that if the ternary complex model of drug action is applicable, then the important cellular influ. ence on affinity might be the local concentration of effector molecules. According to the simplified ternary complex model, the apparent affinity constant &(app) of an agonist A for its receptor is: &(aPP)
=
KIA
+
&A
&A
XT
(1)
where KIA is the receptor constant, KZA is the affinity constant of the RA complex for effector molecule X and XT is the local tissue concentration of the effector molecule. This relationship has recently been further elaborated by Morgan et al4 who pointed out that, with further assumptions, [RAXI could be considered the operational determinant of tissue response. Effector molecule concentration, however, is not the only possible local cellular parameter to influence receptor affinity. For example, it is well known that certain intracellular factors such as ions and possibly the phospholipid content of the membrane microenvironment can regulate affinity5, yet these p;i;:neters do not form part of the proposed ternary complex. In fact K~A, the true receptor affinity, simple as this might be in concept, probably cannot be accurately determined at the moment because the receptor can only be adequately assessed under experimental circumstances that might influence this measurement, for example in a phospholipid or detergent environment. It is known that the receptor is associated with molecuies, e.g. phospholipids, that probably influence the three-dimensional
shape of the agonist recognition site. Thus, Eqn 1 may lack an important element, specifically the environmental influence on the receptor, the receptor-effector complex, or both. Agonist &(app) for the 01~adrenoceptor varies not only between the same tissue in different locations in the same species, but between the same tissue in different species, in the same tissue during maturation, between different individuals of the same species, as the result of disease and with the technique used to prepare tissues for affinity determination. In addition, there is increasing evidence for variation of the affinity of antagonists for the cul-adrenoceptors’. In the face of such diversity of one of the essential characteristics that determine receptor-mediated response, it might well be asked how a satisfactory comprehensive classification can be receptor achieved. It might be that an approach completely different from that presently employed will be necessary. A receptor might have to be described by an affinity profile determined under prescribed circumstances-an affinity profile to key ligands. The true affinity of a receptor molecule is an important chemical feature; however, the affinity of the receptor in situ, the K*(app) is the important functional element. JOHN AND
S.
MARTIN
A.
BEVAN
SHREEVE
Depnrfmentof Pharmncology, University Vermont, Bzrlilrgforz,VT 05405, USA.
References 1 Mackay, D. (1988) Trends 2 3 4 5
Ph~rmacol.
of
Sci.
9, 156-157 Bevan, J. A., Bevan, R. D., Kite, K. and Oriowo, M. A. (1988) Trends PharmacoL Sci. 9, 87-89 Bevan, J. A., Oriowo, M. A. and Bevan, R. D. (1986) Science 234, 196-197 Morgan, P. H., Lutz. M. W. and Kenakin. T. P. (19881 Tretzds Phnmmcol. Sri. 9, 551-352 ’ Bevan, J A., Bevan, R. D. and Shreeve, S. M. FASEB I. (in press)