Dopamine Receptors and Monoamine Oxidase as Virion Receptors

DOPAMINE RECEPTORS AND MONOAMINE OXIDASE AS VIRION RECEPTORS EDWARD G. SHASKAN* LARS ORELANDA and GORAN WADELLt Infection does not always result in clinical disease. It is evident that several complex factors constitute the phenomenon of "host resistance" and these, including a variety of macro- and microenvironmental and genetic factors, ultimately interact to be expressed variously as "immunocompetency " of the individual or simply "disease" [I]. Significant roles for recognition sites (e.g., receptors), which are assimilated within membrane barriers between cells, organelles, and environment, were clearly evident in the writings of René Dubos [1; see, e.g., chaps. 3, 4]. Many neurotransmitter substances have been reported to each be associated with a multiplicity of receptor sites (reviewed in [2, 3]). We have chosen to focus upon dopamine (DA; 3-hydroxytyramine) as a primordial ligand for which there now exists a multiplicity of receptor sites. Extrapolation to other neurotransmitter systems should be possible, however, since there is published evidence for the involvement ofother neurotransmitters in pathogenesis of viral infections, including serotonin [4], epinephrine [5], acetylcholine [6], and endorphins [7]. Indeed, there is direct evidence for nicotinic acetylcholine receptors on mouse diaphragm as receptors for rabies virus [6]. The Hypothesis Dopamine receptors are also viral (virion) receptors. Some dopamine receptors are better viral receptors than others. Multiplicity ofdopamine This work is dedicated to the memory of René Dubos, 1901-1982. The authors gratefully acknowledge Dr. Zelig Dolinsky for helpful discussions during formulation of some theoretical aspects of this manuscript. They thank Jane Shaskan for manuscript preparation , reference retrieval, and assistance, and Drs. Mark Ballow, Howard A. Bern, and Irwin H. Lepow for constructive comments and helpful suggestions. Funds were made available by the Department of Pharmacology, University of Umea, Sweden, and the Swedish Medical Research Council (no. 41-45). * Department of Psychiatry, University of Connecticut Health Center, Farmington, Connecticut 06032. t Department of Pharmacology, University of Umea, S 901 87 Umea, Sweden. t Department of Virology, University of Umea, S 901 87 Umea, Sweden.© 1984 by The University of Chicago. All rights reserved. 0031-5982/84/2702-0372101 .00 Perspectives inBiology and Medicine, 27, 2 ¦ Winter 1984 | 239 receptors, considered in the light of evolution, supports the hypothesis that an ancestral membrane protein was a primitive viral receptor that initially served some other cellular biological function. Although phylogeny and ontogeny of dopamine receptors are consistent with a long evolutionary history for these proteins, we must await gene sequence analyses in order to infer evolutionary relatedness [8]. We find it useful, however, to consider membrane proteins which possess high affinity and specificity for dopamine to belong, at least, to a functional family. Thus, the membrane-bound enzyme monoamine oxidase may have once possessed receptor-related properties, and, therefore, a corollary of the hypothesis is that monoamine oxidase is an intracellular virion receptor. Backgroundfor the HypothesL· Experiments published from the laboratory of the late George C. Cotzias led to a hypothesis that disposition of brain dopamine (a putative neurotransmitter substance) was intimately related to the development of infectious diseases [9, 10]. In common with the catecholamine theory of affective disorders [11] and the dopamine hypothesis of schizophrenia [12], Cotzias's theory was derived essentially from pharmacologic evidence. For example, chronic L-dopa treatment extends life span in mice [9]. Also, BCG vaccine and Corynebacterium parvum, experimental anti-neoplastic agents, stimulate dopamine-sensitive adenylate cyclase [10]. Despite these insightful inroads, precise relationships between brain dopamine and infectious disease have remained largely conjectural . Recent reviews of phenomenology and laboratory-generated experiments lend credibility to a brain-immune system axis [13, 14]. A largely empirical effort, however, is devoted to evaluation of monoaminergic systems, especially in hypothamus [15, 16]. Although obvious neuroendocrine roles for dopamine exist [16], these hypotheses have not yielded clear-cut mechanisms. Accordingly, we wondered whether the same pharmacological evidence supporting a brain dopamine-immune system axis could be interpreted as a direct action of "dopaminergic" agents upon lymphoid cells. Since there is evidence for DA receptors (D-2) on B-lymphocytes [17-19], could these and other "neurotransmitter" binding sites on lymphoid tissue be associated with viruses? Multiple Dopamine Receptors: Specific Constructs Seeman and co-workers [2, 20], focusing on plasma membrane protein-ligand...