BioMol Concepts 2018; 9: 143–154 Review Open Access Rafael Franco*, David Aguinaga, Jasmina Jiménez, Jaume Lillo, Eva Martínez-Pinilla*#, Gemma Navarro# Biased receptor functionality versus biased agonism in G-protein-coupled receptors Journal xyz 2017; 1 (2): 122–135 https://doi.org/10.1515/bmc-2018-0013 b-arrestins or calcium sensors are also provided. Each of receivedThe FirstJuly 19, Decade 2018; accepted (1964-1972) November 2, 2018. the functional GPCR units (which are finite in number) has Abstract:Research Functional Article selectivity is a property of G-protein- a specific conformation. Binding of agonist to a specific coupled receptors (GPCRs) by which activation by conformation, i.e. GPCR activation, is sensitive to the differentMax Musterman, agonists leads Paul to differentPlaceholder signal transduction kinetics of the agonist-receptor interactions. All these mechanisms. This phenomenon is also known as biased players are involved in the contrasting outputs obtained agonismWhat and Is has So attracted Different the interest Aboutof drug discovery when different agonists are assayed. programsNeuroenhancement? in both academy and industry. This relatively recent concept has raised concerns as to the validity and Keywords: conformational landscape; GPCR heteromer; realWas translational ist so value anders of the results am showing Neuroenhancement? bias; firstly cytocrin; effectors; dimer; oligomer; structure. biased agonism may vary significantly depending on the cellPharmacological type and the experimental and Mental constraints, Self-transformation secondly the in Ethic conformationalComparison landscape that leads to biased agonism Introduction hasPharmakologische not been defined. Remarkably,und mentale GPCRs Selbstveränderung may lead to im differential signaling even when a single agonist is used. Functional selectivity is triggered by binding of agonists ethischen Vergleich Here we present a concept that constitutes a biochemical interacting with residues at the orthosteric binding site that property of GPCRs that may be underscored just using results in a conformational change in regions that are close https://doi.org/10.1515/xyz-2017-0010 one agonist, preferably the endogenous agonist. “Biased to the intracellular domains. In silico modeling suggests received February 9, 2013; accepted March 25, 2013; published online July 12, 2014 receptor functionality” is proposed to describe this that the second intracellular loop of the serotonin 5-HT2A effectAbstract: with Inexamples the concept based of theon receptor aesthetic heteromerization formation of knowledge receptor and is involvedits as soon in functional selectivity. The binding andas alternativepossible and splicing. success-oriented Examples ofapplication, regulation insights of final and of profitsdifferent without agonists the results in different conformations of agonist-inducedreference to the outputsarguments based developed on interactionaround 1900. with The mainthe intracelularinvestigation loops, also ultimately resulting in contrasting includes the period between the entry into force and the presentationfunctional in itsoutputs current (1). Residues in transmembrane version. Their function as part of the literary portrayal and domainnarrative 3 technique.are also proposed to be important for functional selectivity in muscarinic (2), cannabinoid (3) and β - *CorrespondingKeywords: Function, author: Rafael transmission, Franco, Molecular investigation, Neurobiology principal, period 2 laboratory. Department of Biochemistry and Molecular adrenergic (4) receptors. Similarly, other regions within Biomedicine, Biology School, University of Barcelona, Spain; the G-protein-coupled receptor (GPCR) structure may Dedicated to Paul Placeholder Centro de Investigación en Red, Enfermedades Neurodegenerativas participate specifically in activating a given signaling (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, E-mail: pathway. This mini-review focuses on the biased receptor [email protected]; Eva Martínez-Pinilla, Departamento de Morfología functionality, a phenomenon that may be underscored by y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Asturias,1 Studies Spain; Instituto and de NeurocienciasInvestigations del Principado de a single agonist leading to different signaling outputs in Asturias (INEUROPA), Asturias, Spain; Instituto de Salud del different cells or even in the same cell. This phenomenon PrincipadoThe main de investigationAsturias (ISPA), alsoAsturias, includes Spain the period between theseemingly entry into involves force and similar mechanisms to those leading Davidthe Aguinaga,presentation Jaume in Lillo: its currentMolecular version. Neurobiology Their laboratory. function as partto biased of the agonismliterary por and- to what is known as “system bias” Department of Biochemistry and Molecular Biomedicine, Biology trayal and narrative technique. (5–7), a concept whose definition and usefulness await School, University of Barcelona, Spain David Aguinaga, Jasmina Jiménez, Gemma Navarro: Centro general consensus. de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED),*Max Musterman: Instituto Institute de Salud of Carlos Marine III, Biology, Madrid, National Spain Taiwan Ocean University, 2 Pei-Ning GemmaRoad Keelung Navarro: 20224, Department Taiwan of (R.O.C), Biochemistry e-mail: and [email protected] Physiology, PharmacyPaul Placeholder: and Food ScienceInstitute School, of Marine University Biology, of National Barcelona, Taiwan Spain Ocean University, 2 Pei-Ning #EqualRoad contribution Keelung 20224, Taiwan (R.O.C), e-mail: [email protected] Journal xyz 2017; 1 (2): 122–135 Open Open Access.Access. © © 2017 2018 Mustermann Rafael Franco and Placeholder, et al., published published by by De De Gruyter. Gruyter. ThisThis work work is is licensed under the Creative Commons Attribution-NonCommercial-NoDerivativeslicensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. 4.0 License. The First Decade (1964-1972) Research Article Max Musterman, Paul Placeholder What Is So Different About Neuroenhancement? Was ist so anders am Neuroenhancement? Pharmacological and Mental Self-transformation in Ethic Comparison Pharmakologische und mentale Selbstveränderung im ethischen Vergleich https://doi.org/10.1515/xyz-2017-0010 received February 9, 2013; accepted March 25, 2013; published online July 12, 2014 Abstract: In the concept of the aesthetic formation of knowledge and its as soon as possible and success-oriented application, insights and profits without the reference to the arguments developed around 1900. The main investigation also includes the period between the entry into force and the presentation in its current version. Their function as part of the literary portrayal and narrative technique. Keywords: Function, transmission, investigation, principal, period Dedicated to Paul Placeholder 1 Studies and Investigations The main investigation also includes the period between the entry into force and the presentation in its current version. Their function as part of the literary por- trayal and narrative technique. *Max Musterman: Institute of Marine Biology, National Taiwan Ocean University, 2 Pei-Ning Road Keelung 20224, Taiwan (R.O.C), e-mail: [email protected] Paul Placeholder: Institute of Marine Biology, National Taiwan Ocean University, 2 Pei-Ning Road Keelung 20224, Taiwan (R.O.C), e-mail: [email protected] Open Access. © 2017 Mustermann and Placeholder, published by De Gruyter. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License. 144 R. Franco et al: Biased GPCR functionality and biased agonism Figure 1: A scheme on functional selectivity based on differential agonist bias. Taken from (13)(fig. 2), with permission. Functional selectivity or biased quantitative aspects of biased agonism appeared later. The agonism: historical perspective effects of different adrenoceptor agonists on two signaling responses, namely regulation of cAMP levels and MAPK “Functional selectivity” and “biased agonism” can be pathway activation, were determined, and the results were used interchangeably and can be considered synonymous summarized as “the results suggest that binding of different to one another. (1,8,9). The following sentence highlights ligands promote distinct conformational changes leading GPCR conformational states as the reason for biased to specific signaling outcomes. Our data therefore clearly agonism: “Different conformations adopted by receptors illustrate that efficacy is a pluridimensional parameter after associating with specific ligands can determine that is not an intrinsic characteristic of a ligand/receptor which intracellular signaling pathways get activated couple” (15). Since then the idea of biased agonism, which and which do not”; this sentence appears in the article is related to therapeutic benefits of functional selectivity, entitled “Functional selectivity, ligand-directed trafficking, has gained momentum both in academia and in drug conformation-specific agonism: What’s in a name” (10). discovery programs in the Pharmaceutical industry The link between biased agonism and stabilization (Figure 1). Current drug discovery programs consider of different receptor conformations leading to diverse GPCR biased agonism and have developed strategies to signaling pathways is also reported in complementary select the most effective biased compound. reviews (11,12). Biased agonism was first “measured” by ranking the