Co-Evolution of Opioid and Adrenergic Ligands and Receptors: Shared, Complementary Modules Explain Evolution of Functional Interactions and Suggest Novel Engineering Possibilities

Abstract

Cross-talk between opioid and adrenergic receptors is well-characterized and involves second messenger systems, the formation of receptor heterodimers, and the presence of extracellular allosteric binding regions for the complementary ligand; however, the evolutionary origins of these interactions have not been investigated. We propose that opioid and adrenergic ligands and receptors co-evolved from a common set of modular precursors so that they share binding functions. We demonstrate the plausibility of this hypothesis through a review of experimental evidence for molecularly complementary modules and report unexpected homologies between the two receptor types. Briefly, opioids form homodimers also bind adrenergic compounds; opioids bind to conserved extracellular regions of adrenergic receptors while adrenergic compounds bind to conserved extracellular regions of opioid receptors; opioid-like modules appear in both sets of receptors within key ligand-binding regions. Transmembrane regions associated with homodimerization of each class of receptors are also highly conserved across receptor types and implicated in heterodimerization. This conservation of multiple functional modules suggests opioid–adrenergic ligand and receptor co-evolution and provides mechanisms for explaining the evolution of their crosstalk. These modules also suggest the structure of a primordial receptor, providing clues for engineering receptor functions.

Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction

“…Evidence from binding studies demonstrates that the extracellular binding sites on both the adrenergic and opioid receptors share, to some extent, affinity for both opioids and adrenergic drugs [85][86][87]89]. This observation is consistent with the observation that there are metastable binding sites for opioids [90][91][92][93] and for adrenergic drugs [74,94,95] located in the extracellular regions of both types of receptor that may act as a sort of staging platform for guiding the ligand into its high-affinity orthosteric pocket.…”

“…This observation is consistent with the observation that there are metastable binding sites for opioids [90][91][92][93] and for adrenergic drugs [74,94,95] located in the extracellular regions of both types of receptor that may act as a sort of staging platform for guiding the ligand into its high-affinity orthosteric pocket. Indeed, the mutual affinity of opioid receptors for adrenergic compounds and adrenergic receptors for opioid compounds appears to be due to the origins of both receptor classes from a common evolutionary origin [89].…”

“…Thus, as in Figures 1 and 2, the result of co-stimulation of ADR with an adrenergic and opioid drug is to enhance the adrenergic activity (whether agonistic or antagonistic) at lower concentrations of the adrenergic drug and to increase the duration of the resulting activity. Model based on data from [88,89,114].…”

‘Evolutionary poker’: an agent‐based model of interactome emergence and epistasis tested against Lenski's long‐term E. coli experiments

“…Our research group has proposed that various forms of complementarity (molecular, metabolic, etc.) might play key roles in stable module formation, which, in turn, selects for functional interactomes (Norris & Root‐Bernstein, 2009; Root‐Bernstein, 2005; Root‐Bernstein & Churchill, 2021; Root‐Bernstein & Dillon, 1997; Root‐Bernstein & Root‐Bernstein, 2016). Integrating such biological mechanisms into EPOKER or other LTEE models will be a future challenge.…”

“…We know many of these intermediate levels of organization: enzyme–substrate pairs cluster into diazyme complexes; multiple sets of receptor–ligand pairs regulate each other's activity by clustering into homo‐ and heterodimers within lipid rafts; the self‐organization and replication of the Golgi apparatus; and cell‐adhesion molecules mediating embryological development processes. None of this clustering, self‐assembly and self‐organization is determined at the level of the genes but rather through specific molecular, supra‐molecular, cellular interactions or tissue/organ organization, often initiated and regulated by various forms of molecular complementarity (Norris & Root‐Bernstein, 2009; Root‐Bernstein, 2005; Root‐Bernstein & Churchill, 2021; Root‐Bernstein & Dillon, 1997). Each of these hierarchical levels of organization would thus seem to require the emergence of a novel type of selection for its correspondingly new type of clustering.…”