20 research outputs found
Temperature and friction fluctuations inside a harmonic potential
In this article we study the trapped motion of a molecule undergoing diffusivity fluctuations inside a harmonic potential. For the same diffusing-diffusivity process, we investigate two possible interpretations. Depending on whether diffusivity fluctuations are interpreted as temperature or friction fluctuations, we show that they display drastically different statistical properties inside the harmonic potential. We compute the characteristic function of the process under both types of interpretations and analyze their limit behavior. Based on the integral representations of the processes we compute the mean-squared displacement and the normalized excess kurtosis. In the long-time limit, we show for friction fluctuations that the probability density function (PDF) always converges to a Gaussian whereas in the case of temperature fluctuations the stationary PDF can display either Gaussian distribution or generalized Laplace (Bessel) distribution depending on the ratio between diffusivity and positional correlation times
Selective and WashâResistant Fluorescent Dihydrocodeinone Derivatives Allow SingleâMolecule Imaging of ÎŒâOpioid Receptor Dimerization
ÎŒâOpioid receptors (ÎŒâORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how ÎŒâORs produce specific effects in living cells. We developed new fluorescent ligands based on the ÎŒâOR antagonist Eâpânitrocinnamoylaminoâdihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved singleâmolecule imaging of ÎŒâORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of ÎŒâORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that ÎŒâORs interact with each other to form shortâlived homodimers on the plasma membrane. This approach provides a new strategy to investigate ÎŒâOR pharmacology at singleâmolecule level
Selective and washâresistant fluorescent dihydrocodeinone derivatives allow singleâmolecule imaging of ÎŒâopioid receptor dimerization
ÎŒâOpioid receptors (ÎŒâORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how ÎŒâORs produce specific effects in living cells. We developed new fluorescent ligands based on the ÎŒâOR antagonist Eâpânitrocinnamoylaminoâdihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved singleâmolecule imaging of ÎŒâORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of ÎŒâORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that ÎŒâORs interact with each other to form shortâlived homodimers on the plasma membrane. This approach provides a new strategy to investigate ÎŒâOR pharmacology at singleâmolecule level
Filamin A organizes Îłâaminobutyric acid type B receptors at the plasma membrane
The γ-aminobutyric acid type B (GABA(B)) receptor is a prototypical family C G protein-coupled receptor (GPCR) that plays a key role in the regulation of synaptic transmission. Although growing evidence suggests that GPCR signaling in neurons might be highly organized in time and space, limited information is available about the mechanisms controlling the nanoscale organization of GABA(B) receptors and other GPCRs on the neuronal plasma membrane. Using a combination of biochemical assays in vitro, single-particle tracking, and super-resolution microscopy, we provide evidence that the spatial organization and diffusion of GABA(B) receptors on the plasma membrane are governed by dynamic interactions with filamin A, which tethers the receptors to sub-cortical actin filaments. We further show that GABA(B) receptors are located together with filamin A in small nanodomains in hippocampal neurons. These interactions are mediated by the first intracellular loop of the GABA(B1) subunit and modulate the kinetics of Gα(i) protein activation in response to GABA stimulation
How Carvedilol activates ÎČ<sub>2</sub>-adrenoceptors
Carvedilol is among the most effective ÎČ-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of ÎČ(1)-adrenoceptors, arrestin-biased signalling via ÎČ(2)-adrenoceptors is a molecular mechanism proposed to explain the survival benefits. Here, we offer an alternative mechanism to rationalize carvedilolâs cellular signalling. Using primary and immortalized cells genome-edited by CRISPR/Cas9 to lack either G proteins or arrestins; and combining biological, biochemical, and signalling assays with molecular dynamics simulations, we demonstrate that G proteins drive all detectable carvedilol signalling through ÎČ(2)ARs. Because a clear understanding of how drugs act is imperative to data interpretation in basic and clinical research, to the stratification of clinical trials or to the monitoring of drug effects on the target pathway, the mechanistic insight gained here provides a foundation for the rational development of signalling prototypes that target the ÎČ-adrenoceptor system
Non-Gaussian diffusion of mixed origins
International audienceThe properties of diffusion processes are drastically affected by hetero-geneities of the medium that can induce non-Gaussian behavior of the propagator in contrast with the idealized realm of Brownian motion. In this paper we analyze the diffusion propagator when distinct origins of heterogeneity (e.g. time-fractional diffusion, diffusing diffusivity, distributed diffusivity across a population) are combined. These combinations allow one to describe new classes of strongly heterogeneous processes relevant to biology. Based on a combined subordination technique, we obtain the exact propagator for different instructive examples. This approach is then used to calculate analytically the first-passage time statistics (on half-real line and in any bounded domain) for a particle undergoing non-Gaussian diffusion of mixed origins
Diffusion-limited reactions in dynamic heterogeneous media
âDiffusing diffusivityâ concept has been recently put forward to account for rapid structural rearrangements in soft matter and biological systems. Here the authors propose a general mathematical framework to compute the distribution of first-passage times in a dynamically heterogeneous medium