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Biochemistry. Biokhimiia Oct 2023The diversity of the retinal-containing proteins (rhodopsins) in nature is extremely large. Fundamental similarity of the structure and photochemical properties unites... (Review)
Review
The diversity of the retinal-containing proteins (rhodopsins) in nature is extremely large. Fundamental similarity of the structure and photochemical properties unites them into one family. However, there is still a debate about the origin of retinal-containing proteins: divergent or convergent evolution? In this review, based on the results of our own and literature data, a comparative analysis of the similarities and differences in the photoconversion of the rhodopsin of types I and II is carried out. The results of experimental studies of the forward and reverse photoreactions of the bacteriorhodopsin (type I) and visual rhodopsin (type II) rhodopsins in the femto- and picosecond time scale, photo-reversible reaction of the octopus rhodopsin (type II), photovoltaic reactions, as well as quantum chemical calculations of the forward photoreactions of bacteriorhodopsin and visual rhodopsin are presented. The issue of probable convergent evolution of type I and type II rhodopsins is discussed.
Topics: Rhodopsin; Bacteriorhodopsins; Photochemistry
PubMed: 38105022
DOI: 10.1134/S0006297923100097 -
Molecules (Basel, Switzerland) Aug 2023G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active... (Review)
Review
G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activated agonist-receptor G-protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and μ opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling-proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). The hypothesis is proposed that ligand-free signaling of 5-HT2A receptors mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close the gaps in our knowledge of ligand-free GPCR signaling.
Topics: Signal Transduction; Cell Membrane; Rhodopsin; Receptors, Ghrelin; Analgesics, Opioid; Ligands
PubMed: 37687205
DOI: 10.3390/molecules28176375 -
British Journal of Pharmacology May 2024GPR84 is an understudied rhodopsin-like class A G protein-coupled receptor, which is arousing particular interest from a therapeutic perspective. Not least this reflects... (Review)
Review
GPR84 is an understudied rhodopsin-like class A G protein-coupled receptor, which is arousing particular interest from a therapeutic perspective. Not least this reflects that gpr84 expression is significantly up-regulated following acute inflammatory stimuli and in inflammatory diseases, and that receptor activation plays a role in regulating pro-inflammatory responses and migration of cells of the innate immune system such as neutrophils, monocytes, macrophages and microglia. Although most physiological responses of GPR84 reflect receptor coupling to G-proteins, several studies indicate that agonist-activated GPR84 can recruit arrestin adaptor proteins and this regulates receptor internalisation and desensitisation. To date, little is known on the patterns of either basal or ligand regulated GPR84 phosphorylation and how these might control these processes. Here, we consider what is known about the regulation of GPR84 signalling with a focus on how G protein receptor kinase-mediated phosphorylation regulates arrestin protein recruitment and receptor function. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.
Topics: Arrestin; Macrophages; Phosphorylation; Receptors, G-Protein-Coupled; Signal Transduction; Humans
PubMed: 37085331
DOI: 10.1111/bph.16098 -
BioEssays : News and Reviews in... Sep 2023The photocycle of visual opsins is essential to maintain the light sensitivity of the retina. The early physical observations of the rhodopsin photocycle by Böll and... (Review)
Review
The photocycle of visual opsins is essential to maintain the light sensitivity of the retina. The early physical observations of the rhodopsin photocycle by Böll and Kühne in the 1870s inspired over a century's worth of investigations on rhodopsin biochemistry. A single photon isomerizes the Schiff-base linked 11-cis-retinylidene chromophore of rhodopsin, converting it to the all-trans agonist to elicit phototransduction through photoactivated rhodopsin (Rho*). Schiff base hydrolysis of the agonist is a key step in the photocycle, not only diminishing ongoing phototransduction but also allowing for entry and binding of fresh 11-cis chromophore to regenerate the rhodopsin pigment and maintain light sensitivity. Many challenges have been encountered in measuring the rate of this hydrolysis, but recent advancements have facilitated studies of the hydrolysis within the native membrane environment of rhodopsin. These techniques can now be applied to study hydrolysis of agonist in other opsin proteins that mediate phototransduction or chromophore turnover. In this review, we discuss the progress that has been made in characterizing the rhodopsin photocycle and the journey to characterize the hydrolysis of its all-trans-retinylidene agonist.
Topics: Humans; Rhodopsin; Photophobia; Retinaldehyde; Retina
PubMed: 37454357
DOI: 10.1002/bies.202300068 -
Physiology (Bethesda, Md.) Jan 2024One of the biggest environmental alterations we have made to our species is the change in the exposure to light. During the day, we typically sit behind glass windows... (Review)
Review
One of the biggest environmental alterations we have made to our species is the change in the exposure to light. During the day, we typically sit behind glass windows illuminated by artificial light that is >400 times dimmer and has a very different spectrum than natural daylight. On the opposite end are the nights that are now lit up by several orders of magnitude. This review aims to provide food for thought as to why this matters for humans and other animals. Evidence from behavioral neuroscience, physiology, chronobiology, and molecular biology is increasingly converging on the conclusions that the biological nonvisual functions of light and photosensory molecules are highly complex. The initial work of von Frisch on extraocular photoreceptors in fish, the identification of rhodopsins as the molecular light receptors in animal eyes and eye-like structures and cryptochromes as light sensors in nonmammalian chronobiology, still allowed for the impression that light reception would be a relatively restricted, localized sense in most animals. However, light-sensitive processes and/or sensory proteins have now been localized to many different cell types and tissues. It might be necessary to consider nonlight-responding cells as the exception, rather than the rule.
Topics: Humans; Animals; Photoreceptor Cells, Invertebrate; Cryptochromes
PubMed: 37905983
DOI: 10.1152/physiol.00017.2023 -
Nature Communications Aug 2023Rhodopsin is a prototypical G protein-coupled receptor (GPCR) critical for vertebrate vision. Research on GPCR signaling states has been facilitated using llama-derived...
Rhodopsin is a prototypical G protein-coupled receptor (GPCR) critical for vertebrate vision. Research on GPCR signaling states has been facilitated using llama-derived nanobodies (Nbs), some of which bind to the intracellular surface to allosterically modulate the receptor. Extracellularly binding allosteric nanobodies have also been investigated, but the structural basis for their activity has not been resolved to date. Here, we report a library of Nbs that bind to the extracellular surface of rhodopsin and allosterically modulate the thermodynamics of its activation process. Crystal structures of Nb2 in complex with native rhodopsin reveal a mechanism of allosteric modulation involving extracellular loop 2 and native glycans. Nb2 binding suppresses Schiff base deprotonation and hydrolysis and prevents intracellular outward movement of helices five and six - a universal activation event for GPCRs. Nb2 also mitigates protein misfolding in a disease-associated mutant rhodopsin. Our data show the power of nanobodies to modulate the photoactivation of rhodopsin and potentially serve as therapeutic agents for disease-associated rhodopsin misfolding.
Topics: Animals; Rhodopsin; Single-Domain Antibodies; Camelids, New World; Ear Auricle; Gene Library
PubMed: 37626045
DOI: 10.1038/s41467-023-40911-9 -
Cells Jun 2023The photoreceptor outer segment is a highly specialized primary cilium that is essential for phototransduction and vision. Biallelic pathogenic variants in the...
The photoreceptor outer segment is a highly specialized primary cilium that is essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in , there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of -related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids by modulating the expression of rhodopsin and by targeting cilia and synaptic plasticity pathways. This work sheds light on the mechanism of action of eupatilin and supports its potential as a variant-independent approach for -associated ciliopathies.
Topics: Humans; Cilia; Antigens, Neoplasm; Neoplasm Proteins; Rhodopsin; Cytoskeletal Proteins; Flavonoids; Ciliopathies
PubMed: 37371046
DOI: 10.3390/cells12121575 -
Nature Structural & Molecular Biology Jul 2023Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have...
Proton transport is indispensable for cell life. It is believed that molecular mechanisms of proton movement through different types of proton-conducting molecules have general universal features. However, elucidation of such mechanisms is a challenge. It requires true-atomic-resolution structures of all key proton-conducting states. Here we present a comprehensive function-structure study of a light-driven bacterial inward proton pump, xenorhodopsin, from Bacillus coahuilensis in all major proton-conducting states. The structures reveal that proton translocation is based on proton wires regulated by internal gates. The wires serve as both selectivity filters and translocation pathways for protons. The cumulative results suggest a general concept of proton translocation. We demonstrate the use of serial time-resolved crystallography at a synchrotron source with sub-millisecond resolution for rhodopsin studies, opening the door for principally new applications. The results might also be of interest for optogenetics since xenorhodopsins are the only alternative tools to fire neurons.
Topics: Protons; Proton Pumps; Ion Transport
PubMed: 37386213
DOI: 10.1038/s41594-023-01020-9