Hormone and anti-hormone action at the target cell

Nature Vol. 260 March 25 1916 288 to leak ATP at 8 min after infection at the same rate as the infected PifA +B+ cell, and yet ribosomes are not immediately damaged, and protein synthesis continues for an additional 5 min. Several matters need to be cleared up, therefore, before we will know whether or not the permeability hypothesis holds water. The results of Blumberg et a/. may indicate that membrane damage is only a partial explanation for the abortive infection, or they may mean that leakage of A TP is an inadequate assay for the total amount of membrane damage sustained during infection of a wild-type male. Part of the difficulty in distinguishing between these two alternatives is that we do not know whether the Pif mutants really define two genes, or whether the PifA-B+ mutant simply contains a crippled Pif gene. Jn addition, it will help in evaluating the relative importance of ribosome damage and membrane damage when we know whether RNA synthesis is affected in the Pif A -B+ male relative to the wild-type male, and whether or not ribosomes in ·t he Pif A -B+ male remain healthy even after the infection aborts. A successful virus infection represents a very carefully balanced relationship between the virus and its host, which, in this case, has run amuck. There seems to be a T7 gene(s) which when expressed in male E. coli leads to permeability changes, and may ultimately he involved directly or indirectly in the observed paralysis of macromolecular synthesis and damage to ribosomes. Espedally because of the implied ~nteraction with the cell envelope, it will be interesting to discover the normal role of this phage gene during T7 infection of female cells. Hormone and antihormone action at the target cell from Tom Blundell A Dahlem Workshop on Antihormones and the Target Cell was held in Berlin on February 16- 20, 1976. The proceedings will be published by Dahlem Konfcrenzen. SPECTACULAR advances rin our knowledge have recently resulted from studies of hormone receptors. This is not only true for the membrane receptors of polypeptide hormones and catecholamines, but also for the intra- cellular receptors of steroid hormones, v~tamin D metabolites and thyroid hormone. Can these new insights into the field of receptors now be useful in the design of biological tools and therapeutic agents? This question was central to the Fourth Dahlem Workshop on "Hormone and Antihormone Action at the Target Cell" held in Berlin recently at which endocrinologists with a wide range of interests in hormone receptor interactions gathered together with biophysicists, molecular biologists and protein biochemists. Unfamilianity with the new nolecture format of the Dahlem meetings resulted in a hesitant beginning but the discussions soon warmed up wi,t h the help of ·the generous hospital1ity and efficient organisation of Silke Bernhard and her colleagues. In the following days the debate ranged over a number of difficult and neglected areas in the study of hormone receptor interactions, and demons-trated the need for discussions between the various scientific disciplines represented. The term "antihormone" refers to all those substances that act to att-enuate hormone-induced responses regardless of their mechanism. Thus mechanisms changing the affinity of the receptor for the hormone by direct competitive binding of antagonists or indeed by allosteric effectors are included, as well as factors which affect hormone availability at the target cell, loss of receptors, and regulation of receptor synthesis. For steroid receptors a combined steric and allosteric model presented by M. Sherman (University of California Medical Center) seemed to be ver)l us·eful. In this model, a dimeric receptor can exist in two conformational states, one of which is inaotive because the receptor molecule cannot enter the nuclei or cannot bind to the proper genomic sites or is not released normally from the nuclei. A steroid that binds the inactive state is an antagonist, and one that binds the active state Is an agonist. Any steroid that exhibits some affinity for both states is a partial agonist because under some conditions it will be a suboptimal inducer of the function studied, but in the presence of a pure agonist it may act as a partial antagonist. Thus the antagonism by progesterone of glucocorticoid-induced tyrosine aminotransferase in hepatoma cells results from the formation of a glucocorticoid receptor-progesterone complex which does not undergo translocation to the nucleus. On the other hand the ability of steroids to act as partial agon:ists is exemplified by the par·tial action of 11-deoxycortisol on sodium transport. In this system aldosterone binds exclusively to the active stale while the 11-deoxycortisol binds © 1976 Nature Publishing Group about half as well to the active and inactive states. In the field of membrane receptors models seemed to be less in fashion and there was general emphasis on the need to define the macromolecular components more precisely. No hormone receptor or eukaryotic adenylate cyclase has as yet been purified although a characterisation using appropriate detergents as solubilising agents has been achieved for a number of membrane bound proteins such as Ca2+ -ATPase, glycophorin and the acetylchol·ine receptor. C. Tanford (Duke University Medical Center) emphasised the need for using detergents such as Tween 80 with long hydrophobic tails which simulate the membrane bilayer but pointed out that a rather different detergent, for example deoxycholate, may be preferable for ini•tial disruption and fragmentation of the membrane. The presence of detergent bound to a protein receptor does not interfere with the determination of molecular weight using sedimentation equilibrium. With pure preparations, the conformational state of occupied and unoccupied receptors can be defined and the design of antihormones carried out on a more rational basis. Many hormones have not evolved to fit best the receptor of the same species. Although there .is good species specificity with vasopressin analogues, salmon calcitonin has high aotivity in man when compared with human calcitonin. In a similar way insulin receptors from different species bind insulins from various animals with similar relative affiniHes. J. Roth (National Insti,tutes of Heal.th, Bethesda) suggested that the receptor proteins may be under strong evolutionary constraints because •they have other functions essential to the membrane. Thus similar molecules may exist in the membranes of cells to which the hormone has no biological response and even in prokaryotic cells. This would provide an explana1tion for the reported activity of insulin and glucagon on bacteria and algae. It also suggests that it may be worthwhile to explore the pos5ribil:i,ty of synthesising molecules which are better agonists than the natural hormone. Another observation that gave rise to much discussion was the recent report on the enkephalin (...truncated)