The Concept of Allosteric Interaction and Its Consequences for the Chemistry of the Brain

Abstract

Throughout this Reflections article, I have tried to follow up on the genesis in the 1960s and subsequent evolution of the concept of allosteric interaction and to examine its consequences within the past decades, essentially in the field of the neuroscience. The main conclusion is that allosteric mechanisms built on similar structural principles operate in bacterial regulatory enzymes, gene repressors (and the related nuclear receptors), rhodopsin, G-protein-coupled receptors, neurotransmitter receptors, ion channels, and so on from prokaryotes up to the human brain yet with important features of their own. Thus, future research on these basic cybernetic sensors is expected to develop in two major directions: at the elementary level, toward the atomic structure and molecular dynamics of the conformational changes involved in signal recognition and transduction, but also at a higher level of organization, the contribution of allosteric mechanisms to the modulation of brain functions. Theory in BiologyI n the physical sciences, there is a long tradition of theory and model building; the advancement of the discipline has relied and still relies on an active interplay between theory and experimental studies and between the development of novel technologies and conceptual invention. In the biological sciences, a similar tradition exists, but it is not as systematic. The frequent enthusiasm for new techniques without explicit theoretical perspectives often hides an impoverished theoretical landscape where original hypotheses or ideas are rare. In my view, the theoretical objectives should precede, or be concomitant with, the technological and experimental means. According to Claude Bernard, "the experimenter who does not know what he is looking for will not understand what he finds" (1).1 The reasons for the difficulties encountered with the biological sciences possibly lie in the fact that the objects of biology are highly differentiated with multiple, intricate levels of organization. The identification of common conceptual rules further hinges on the considerable structural and functional diversity of the biological objects. Thus, there is the constant dilemma, often split between scientists, about the universality or the singularity of the objects they investigate. In this context, I have selected as a tentative common rule the concept of allosteric interaction and its consequences on the molecular chemistry of proteins, going from bacterial regulatory enzymes up to the nervous system and, tentatively, the higher functions of the brain.The circumstances of my personal life have been such that as an adolescent, I was already exposed to theory through the teaching of an exceptional professor of natural sciences, Jean Bathellier, who introduced me to the idea of biological evolution. This experience deeply influ-1 The full quote (see Ref. 255) is, "Empiricism may serve to accumulate facts, but it will never build science. The experimenter who does not know what he is looking for will not understand what he finds."

Binding site location on GABAA receptors determines whether mixtures of intravenous general anaesthetics interact synergistically or additively in vivo

“…The concept that general anaesthetics interact allosterically with function in the pentameric ligand‐gated ion channel superfamily has long been recognized (Olsen, ; Changeux, ). Our work and that of Akk and colleagues adds to this concept by considering allosteric interactions between anaesthetic sites (Cao et al, ).…”

Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders

“…Interestingly, CNS drug discovery efforts to target ligand-gated ion channel neurotransmitter receptors have focused primarily on developing ligands that interact with allosteric sites that are topographically distinct from the orthosteric neurotransmitter site 5,6 . By binding to allosteric sites, such ligands can act as either positive allosteric modulators (PAMs) or negative allosteric modulators (NAMs) to potentiate or inhibit activation of the receptor by the endogenous agonist, respectively.…”

Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes

“…By definition, all iso-receptors bind the same endogenous ligand, and in a biological sense, they could have evolved to enable the organism to react differently to such a ligand. In fact, mutations in some subunits can directly affect the binding site, possibly resulting in affinity changes that often are exploited experimentally for identifying receptor subtypes (Agnati et al, 1980;Rudolph and Knoflach, 2011;Changeux, 2013a However, the functional features of a receptor can also be modified by mutations in domains not involved in ligand recognition since GPCR can show changes in the response to allosteric effectors, i.e. to ligands binding to sites different from the othosteric binding site (Kenakin and Miller, 2010).…”

“…The basic phenomenon involved in RRI is allostery and cooperativity of membrane receptors as pointed out by Changeux in 1964 by the farsighted proposal of extending the concept of cooperativity to 'membrane phenomena involved in the recognition of communication signals and their transmission' (Changeux, 2013a).…”