Receptors, Volume 3, Issue 1 (March 2024) – 6 articles

Receptology, the science of receptors, is a multidimensional field of research which can be dissected into biosynthesis, membrane sorting, ligand binding and signal transduction. Plasma membrane receptors connect the cells with their environment and transmit signals that are translated into biological information. The historical paradigm of ligand–receptor interactions is the lock-and-key model. This model presupposes that both partners have a precise 3D shape that perfectly fits together to form the ligand–receptor complex. However, this simple model suffers from severe limitations due to several levels of simplifications: (i) water molecules and membrane lipids are not considered; (ii) not all ligands have a stable 3D structure; (iii) the ligand-binding pocket of the receptor is often flexible and conformationally rearranged after the initial binding step (induced fit mechanism) and/or subjected to conformational selection by the ligand; (iv) there are signal transduction mechanisms which can be either purely mechanical (conformational change of the receptor induced after binding of the ligand), lipid-assisted (e.g., by raft lipids such as cholesterol or gangliosides), or in some instances of quantic nature (detection of odorant molecules). The aim of the present review is to challenge the old paradigms and present new concepts of membrane receptology that consider the impact of critical parameters such as water molecules, membrane lipids, electrostatic surface potential and quantum mechanisms. Full article

The development of potent BRAF inhibitors has revolutionized the treatment of BRAF mutant cancers, in particular, melanomas. However, BRAF mutant cancers of other entities, e.g., colorectal cancers, display distinctly reduced responses to BRAF inhibitors. In addition, the emergence of cancer resistance to BRAF inhibitor treatment poses a severe problem. The reactivation of MAPK/ERK signaling was identified as an important mode of BRAF inhibitor resistance. Receptor tyrosine kinases (RTKs), which are prominent anticancer drug targets in their own right, play a crucial role in the development of drug resistance to BRAF inhibitors and the reactivation of MAPK/ERK signal transduction, as well as the establishment of bypassing signaling pathways. MAPK reactivation can occur via increased expression of RTKs, altered RTK signaling, and post-translational processes, among others. This review summarizes the influence of pertinent RTKs on BRAF mutant cancers and BRAF inhibitor resistance and outlines possible and proven ways to circumvent BRAF-associated resistance mechanisms. Full article

The involvement of the prefrontal cortical dopaminergic system in the psychopathology of epilepsies and comorbid conditions such as autism spectrum disorder (ASD) still needs to be explored. We used autoradiography to study the D1-like (D1DR) and D2-like (D2DR) receptor binding density in the prefrontal cortex of normal Wistar rats and Wistar-derived strains with generalized convulsive and/or non-convulsive epilepsy. WAG/Rij rats served as a model for non-convulsive absence epilepsy, WAG/Rij-AGS as a model of mixed convulsive/non-convulsive form, and KM strain was a model for convulsive epilepsy comorbid with an ASD-like behavioral phenotype. The prefrontal cortex of rats with any epileptic pathology studied demonstrated profound decreases in binding densities to both D1DR and D2DR; the effects were localized in the primary and secondary anterior cingulate cortices, and adjacent regions. The local decreased D1DR and D2DR binding densities were independent of (not correlated with) each other. The particular group of epileptic rats with an ASD-like phenotype (KM strain) displayed changes in the lateral prefrontal cortex: D1DR were lowered, whereas D2DR were elevated, in the dysgranular insular cortex and adjacent regions. Thus, epilepsy-related changes in the dopaminergic system of the rat archeocortex were localized in the medial prefrontal regions, whereas ASD-related changes were seen in the lateral prefrontal aspects. The findings point to putative local dopaminergic dysfunctions, associated with generalized epilepsies and/or ASD. Full article

Almost exactly 35 years after starting to work with the human glucocorticoid receptor (hGR), it is interesting for me to re-evaluate the data and results obtained in the 1980s–1990s with the benefit of current knowledge. What was understood then and how can modern perspectives increase that understanding? The hGR’s tau1c activation domain that we delineated was an enigmatic protein domain. It was apparently devoid of secondary and tertiary protein structures but nonetheless maintained gene activation activity in the absence of other hGR domains, not only in human cells but also in yeast, which is evolutionarily very divergent from humans and which does not contain hGR or other nuclear receptors. We now know that the basic machinery of cells is much more conserved across evolution than was previously thought, so the hGR’s tau1c domain was able to utilise transcription machinery components that were conserved between humans and yeast. Further, we can now see that structure–function aspects of the tau1c domain conform to a general mechanistic framework, such as the acidic exposure model, that has been proposed for many activation domains. As for many transcription factor activation domains, it is now clear that tau1c activity requires regions of transient secondary structure. We now know that there is a tendency for positive Darwinian selection to target intrinsically disordered protein domains. It will be interesting to study the distribution and nature of the many single nucleotide variants of the hGR in this respect. Full article

That signaling bias is a n^th level of complexity in the understanding of G protein-coupled receptor (GPCR) activation is a first fact. That its exhaustive description, including the mode d’emploi of its quantitative measurement, remains a challenge is a second fact. That the use of this concept is promising for the design of drug candidates is a third fact. That the translation of signaling biases observed into in vivo specific effects is well documented is a fourth fact. However, the road to apply those aspects of receptology to a systematic description of a ligand and, a fortiori, of a drug candidate, still necessitates a huge body of studies. In the present commentary, the merits of the molecular description of receptor bias signaling are highlighted and the ligand induced-fit impact on GPCR structure, as well as on the functional repertoire of GPCRs, is discussed. An emphasis is given to the practical aspects during drug design, and, thus, the practical limitations of the current approaches, particularly in the context of as soon as the data are transferred to more integrated/living systems, might be a major limitation. Full article

Major depression is related to dysfunction of the GABAergic pathway. Interestingly, the antidepressant fluoxetine modifies GABAergic neurotransmission in human and animal models of depression. However, the effects of norfluoxetine (the main metabolite of fluoxetine) on GABAergic neurotransmission have not yet been studied. Therefore, we explored whether fluoxetine and/or norfluoxetine may regulate GABAergic transmission and whether these substances interact with GABA_A receptors in hippocampal CA1 stratum radiatum interneurons. For these purposes, we recorded the firing profile, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs), and currents induced by GABA puffs in stratum radiatum interneurons using both whole-cell current- and voltage-clamp techniques. Interneurons were selected according with their high firing profile. We found that both fluoxetine and norfluoxetine (at 20 µM) significantly decreased the frequency of sIPSCs without modifying their amplitude and decreased the amplitude of GABA-induced currents. These results indicate that fluoxetine and norfluoxetine decrease GABA release from neurons contacting stratum radiatum interneurons and negatively modulate GABA_A receptors in these interneurons, resulting in their disinhibition, which in turn may contribute to increasing the inhibition of hippocampal CA1 pyramidal neurons. Full article