Biology subjects

Mazor, Y.

Publications and source records attributed to Mazor, Y..

4 recordsLinked to original sources

bioRxiv2023

Attenuation of colitis-induced visceral hypersensitivity and pain by silencing TRPV1-expressing fibers in rat colon

Background and AimsAbdominal pain in patients with inflammatory bowel disease (IBD) is common and debilitating. In our study, we aim to utilize transient receptor potential vanilloid 1 (TRPV1) channels, large-pore cation channels expressed on nociceptors, as a drug delivery system to selectively inhibit visceral nociceptors and thus visceral pain in a rodent model of IBD. MethodsWe induced colitis in rats using intrarectal dinitrobenzene sulfonic acid. Visceral hypersensitivity, spontaneous pain, and responsiveness of the hind paws to noxious heat stimuli were examined before and after the intrarectal application of sodium channel blocker QX-314 alone or together with TRPV1 channel activators or blockers. ResultsIntrarectal co-application of QX-314 with TRPV1 channel activator capsaicin significantly inhibited colitis-induced gut hypersensitivity. Furthermore, in the model of colitis, but not in naive rats, QX-314 alone was sufficient to reverse gut hypersensitivity. The blockade of TRPV1 channels prevented this effect of QX-314. Finally, applying QX-314 alone to the inflamed gut inhibited colitis-induced ongoing pain. ConclusionsSelective silencing of nociceptors by QX-314 entering via exogenously or endogenously activated TRPV1 channels diminish IBD-induced gut hypersensitivity. These results yet again confirm the central role of TRPV1-expressing nociceptive neurons in IBD pain. The lack of QX-314 effect on naive rats suggests its selective analgesic effect in IBD pain. Moreover, our results demonstrating the effect of QX-314 alone imply the role of a tonically active TRPV1 channel in the pathophysiology of IBD pain. This approach provides proof-of-concept for using charged activity blockers for selective and effective blockade of visceral pain.

neuroscience↗

bioRxiv2022

Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain

Activity-dependent structural plasticity of axon initial segment (AIS) regulates neuronal excitability, thus fine-tuning neuronal and overall network output. Here using behavioral, immunohistochemical, electrophysiological and computational approaches, we describe the structural plasticity of AIS in rats superficial spinal cord dorsal horn (SDH) neurons, which underlies inflammatory pain. We show an inflammation-mediated distal shift of the AIS away from the soma in inhibitory but not excitatory SDH neurons, concomitant with the peak of inflammatory pain. This AIS translocation was accompanied by a decrease in excitability of the inhibitory neurons. Following recovery from inflammatory hyperalgesia, the AIS location and neuronal excitability reversed to baseline levels. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of differential inflammation-mediated AIS plasticity, reducing the excitability of inhibitory but not excitatory SDH neurons and contributing to inflammatory hyperalgesia.

neuroscience↗

bioRxiv2021

Structure of Dunaliella Photosystem II reveals conformational flexibility of stacked and unstacked supercomplexes

Photosystem II (PSII) generates an oxidant whose redox potential is high enough to enable water oxidation1,2, a substrate so abundant that it assures a practically unlimited electron source for life on earth3. Our knowledge on the mechanism of water photooxidation was greatly advanced by high-resolution structures of prokaryotic PSII4-6. Here we show high-resolution structures of eukaryotic PSII from the green algae Dunaliella salina at two distinct conformations. The conformers are also present in stacked PSII, exhibiting flexibility that is relevant to the grana formation in chloroplasts of the green lineage. CP29, one of PSII associated light harvesting antennae, plays a major role in distinguishing the two conformations of the supercomplex. We also show that the stacked PSII dimer, a form suggested to support the organization of thylakoid membranes7,8, can appear in many different orientations providing a flexible stacking mechanism for the arrangement of grana stacks in thylakoids. Our findings provide a structural basis for the heterogenous nature of the eukaryotic PSII on multiple levels.

plant biology↗

bioRxiv2021

The structure of the Physcomitrium Patens Photosystem I Reveals a Unique Lhca2 Paralogue replacing Lhca4

The moss Physcomitrium patens diverged from green algae shortly after the colonization of land by ancient plants. This colonization posed new environmental challenges which drove evolutionary processes. The photosynthetic machinery of modern flowering plants is adapted to the high light conditions on land. Red shifted Lhca4 antennae are present in the photosystem I light harvesting complex of many green lineage plants but absent from P. patens. The Cryo-EM structure of the P. patens photosystem I light harvesting complex I supercomplex (PSI-LHCI) at 2.8 [A] reveals that Lhca4 is replaced by a unique Lhca2 paralogue in moss. This PSI-LHCI supercomplex also retains the PsaM subunit, present in cyanobacteria and several algal species but lost in higher plants, and the PsaO subunit responsible for binding light harvesting complex II. The blue shifted Lhca2 paralogue and chlorophyll b enrichment relative to higher plants make the P. patens PSI-LHCI spectroscopically unique among other green lineage supercomplexes. Overall, the structure represents an evolutionary intermediate PSI with the crescent shaped LHCI common in higher plants and contains a unique Lhca2 paralogue which facilitates the mosses adaptation to low light niches.

biochemistry↗