Functional optimization of light-activatable Opto-GPCRs: Illuminating the importance of the proximal C-terminus in G-protein specificity

Leemann, Siri; Kleinlogel, Sonja

doi:10.3389/fcell.2023.1053022

Cited by 6 publications

(3 citation statements)

References 66 publications

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“…Exciting progress has been made toward restoring light sensitivity to degenerated retinas, either by replenishing photoreceptors using stem cells (Mahato et al, 2020), or by conferring light sensitivity onto other neurons in the circuit (Kralik et al, 2022; Leemann & Kleinlogel, 2023; Rodgers et al, 2023; Sahel et al, 2021; van Wyk & Kleinlogel, 2023). Gene therapy effectively targets individual mutations (Bennett et al, 1996; Pang et al, 2008; Tun et al, 2023), but this approach faces the daunting challenge posed by hundreds of different mutations that can cause RP (S. Daiger et al, 2013; Hamel, 2006; McLaughlin et al, 1995; O’Neal & Luther, 2023).…”

Section: Discussionmentioning

confidence: 99%

A metabotropic glutamate receptor agonist enhances visual signal fidelity in a mouse model of retinitis pigmentosa

Li,

Sedlacek,

Nath

et al. 2024

Preprint

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Many inherited retinal diseases target photoreceptors, which transduce light into a neural signal that is processed by the downstream visual system. As photoreceptors degenerate, physiological and morphological changes to retinal synapses and circuitry reduce sensitivity and increase noise, degrading visual signal fidelity. Here, we pharmacologically targeted the first synapse in the retina in an effort to reduce circuit noise without sacrificing visual sensitivity. We tested a strategy to partially replace the neurotransmitter lost when photoreceptors die with an agonist of receptors that ON bipolars cells use to detect glutamate released from photoreceptors. In rd10 mice, which express a photoreceptor mutation that causes retinitis pigmentosa (RP), we found that a low dose of the mGluR6 agonist L-2-amino-4-phosphonobutyric acid (L-AP4) reduced pathological noise induced by photoreceptor degeneration. After making in vivo electroretinogram recordings in rd10 mice to characterize the developmental time course of visual signal degeneration, we examined effects of L-AP4 on sensitivity and circuit noise by recording in vitro light-evoked responses from individual retinal ganglion cells (RGCs). L-AP4 decreased circuit noise evident in RGC recordings without significantly reducing response amplitudes, an effect that persisted over the entire time course of rod photoreceptor degeneration. Subsequent in vitro recordings from rod bipolar cells (RBCs) showed that RBCs are more depolarized in rd10 retinas, likely contributing to downstream circuit noise and reduced synaptic gain, both of which appear to be ameliorated by hyperpolarizing RBCs with L-AP4. These beneficial effects may reduce pathological circuit remodeling and preserve the efficacy of therapies designed to restore vision.

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Section: Discussionmentioning

confidence: 99%

A metabotropic glutamate receptor agonist enhances visual signal fidelity in a mouse model of retinitis pigmentosa

Li,

Sedlacek,

Nath

et al. 2024

Preprint

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“…After the submission of this work, a preprint has appeared that also stressed the importance of ICL3 in G protein coupling efficiency [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Photodynamic Activation of Cholecystokinin 1 Receptor Is Conserved in Mammalian and Avian Pancreatic Acini

Wang

Cui

2023

Biomedicines

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Cholecystokinin 1 receptor (CCK1R) is the only G protein coupled receptor that is activated in type II photodynamic action, but whether this is a property common to both mammalian and avian species is not known. In this work, pancreatic acini were isolated from the rat, mouse, and Peking duck, and photodynamic CCK1R activation was examined. Isolated pancreatic acini were exposed to photosensitizer sulphonated aluminum phthalocyanine (SALPC) and photodynamic action elicited by a brief light-emitting diode (LED 675 nm) pulse (1.5 min); photodynamic CCK1R activation was assessed by Fura-2 fluorescent calcium imaging. Photodynamic action was found to induce persistent calcium oscillations in rat, mouse, and Peking duck pancreatic acini, with the sensitivity order of mouse > rat > Peking duck. Photodynamically-activated CCK1R could be inhibited reversibly by CCK1R antagonist devazepide (1 μM); photodynamic CCK1R activation was blocked by pre-incubation with 1O2 quencher Trolox C (300 µM). The sensitivity of photodynamic CCK1R activation was correlated with the increasing size of the disordered region in intracellular loop 3. These data suggest that photodynamic CCK1R activation is conserved in both mammalian and avian species, as evidenced by the presence of the photodynamic activation motif “YFM” in transmembrane domain 3.

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“…The first Opto-GPCR, chimeric proteins between bovine rhodopsin and β2-AR, were created in 2005 by the Khorana team [ 160 ]. Since then, the original approach of replacing all intracellular loops and the C-terminus has been optimized, and it is now known that only the intracellular loop 3 and the C-terminus are sufficient to activate the desired downstream signaling pathways [ 161 , 162 ]. To date, Opto-GPCR have been exclusively tested in neural systems and have yet to be applied to the cardiovascular system.…”

Section: Perspectivesmentioning

confidence: 99%

Cardiac optogenetics: shining light on signaling pathways

Leemann,

Schneider-Warme,

Kleinlogel

2023

Pflugers Arch - Eur J Physiol

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In the early 2000s, the field of neuroscience experienced a groundbreaking transformation with the advent of optogenetics. This innovative technique harnesses the properties of naturally occurring and genetically engineered rhodopsins to confer light sensitivity upon target cells. The remarkable spatiotemporal precision offered by optogenetics has provided researchers with unprecedented opportunities to dissect cellular physiology, leading to an entirely new level of investigation. Initially revolutionizing neuroscience, optogenetics quickly piqued the interest of the wider scientific community, and optogenetic applications were expanded to cardiovascular research. Over the past decade, researchers have employed various optical tools to observe, regulate, and steer the membrane potential of excitable cells in the heart. Despite these advancements, achieving control over specific signaling pathways within the heart has remained an elusive goal. Here, we review the optogenetic tools suitable to control cardiac signaling pathways with a focus on GPCR signaling, and delineate potential applications for studying these pathways, both in healthy and diseased hearts. By shedding light on these exciting developments, we hope to contribute to the ongoing progress in basic cardiac research to facilitate the discovery of novel therapeutic possibilities for treating cardiovascular pathologies.

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Functional optimization of light-activatable Opto-GPCRs: Illuminating the importance of the proximal C-terminus in G-protein specificity

Cited by 6 publications

References 66 publications

A metabotropic glutamate receptor agonist enhances visual signal fidelity in a mouse model of retinitis pigmentosa

A metabotropic glutamate receptor agonist enhances visual signal fidelity in a mouse model of retinitis pigmentosa

Photodynamic Activation of Cholecystokinin 1 Receptor Is Conserved in Mammalian and Avian Pancreatic Acini

Cardiac optogenetics: shining light on signaling pathways

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