Oncomodulin: The Enigmatic Parvalbumin Protein

Climer, Leslie K.; Cox, Andrew M.; Reynolds, Timothy; Simmons, Dwayne D.

doi:10.3389/fnmol.2019.00235

Cited by 31 publications

(34 citation statements)

References 147 publications

(213 reference statements)

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“…Cochleae were isolated at 0.5, 4, and 24 HPN, and fluorescent antibodies for oncomodulin (OCM) and myosin 7a (MYO7a) 37 were used to quantify OHCs. OCM is an EF-hand calcium binding protein highly expressed in OHCs 38 , and its deletion confers progressive hearing loss 39 To determine the overall number of OCM+ OHCs after noise exposure, cochleae were stained with DAPI and antibodies against OCM, MYO7a or Cytochrome-C (CytC), a mitochondriaassociated hemeprotein strongly expressed in OHCs 40 . Cochleograms were generated for each genotype and timepoint.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…We show a correlation of early and prolonged OCM modulation with cell injury, possibly due to excessive calcium buffering experienced in noise exposure. OCM binds to calcium and is localized to the cuticular plate and cytoplasm of OHCs, likely to regulate their motility 38 . We found that OCM immunoreactivity normally fluctuates at baseline and in response to noise in viable OHCs (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…When modeled in vitro , OCM did not appear to have a direct impact on actin polymerization 54 . There have been no studies to confirm whether OCM protects against oxidative stress and whether it is responsible for multiple functions within OHCs 38 . The majority of OHCs containing fragmented nuclei expressed low OCM levels, making its loss a marker of permanent damage (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Primed to Die: An Investigation of the Genetic Mechanisms Underlying Noise-Induced Hearing Loss and Cochlear Damage in Homozygous Foxo3-knockout Mice

Beaulac

Gilels

Zhang

et al. 2021

Preprint

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The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following a mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo3-het), and Foxo3-knockout (Foxo3-KO) mice to better understand Foxo3's roles in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage, including calcium regulators, oxidative stress, necrosis, and caspase-dependent and independent apoptosis. Lower immunoreactivity of the calcium buffer oncomodulin in Foxo3-KO OHCs correlated with cell loss beginning 4 hours post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3's absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposed Foxo3-KO mice that may contribute to OHC noise susceptibility. Glycerophosphodiester Phosphodiesterase Domain Containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise exposed Foxo3-KO mice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Primed to Die: An Investigation of the Genetic Mechanisms Underlying Noise-Induced Hearing Loss and Cochlear Damage in Homozygous Foxo3-knockout Mice

Beaulac

Gilels

Zhang

et al. 2021

Preprint

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“…Oncomodulin (Ocm) or parvalbumin β (β-PA) is a small (11–12 kDa), acidic (pI < 5), globular vertebrate-specific Ca 2+ -binding protein of the EF-hand superfamily [ 1 , 2 , 3 , 4 ]. The EF-hand domain consists of a 12-residue Ca 2+ -coordinating loop flanked by two amphiphilic α-helices (“helix-loop-helix” motif) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

The Highly Conservative Cysteine of Oncomodulin as a Feasible Redox Sensor

et al. 2021

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Oncomodulin (Ocm), or parvalbumin β, is an 11–12 kDa Ca2+-binding protein found inside and outside of vertebrate cells, which regulates numerous processes via poorly understood mechanisms. Ocm consists of two active Ca2+-specific domains of the EF-hand type (“helix-loop-helix” motif), covered by an EF-hand domain with inactive EF-hand loop, which contains a highly conservative cysteine with unknown function. In this study, we have explored peculiarities of the microenvironment of the conservative Cys18 of recombinant rat Ocm (rWT Ocm), redox properties of this residue, and structural/functional sensitivity of rWT Ocm to the homologous C18S substitution. We have found that pKa of the Cys18 thiol lays beyond the physiological pH range. The measurement of redox dependence of rWT Ocm thiol–disulfide equilibrium (glutathione redox pair) showed that redox potential of Cys18 for the metal-free and Ca2+-loaded protein is of −168 mV and −176 mV, respectively. Therefore, the conservative thiol of rWT Ocm is prone to disulfide dimerization under physiological redox conditions. The C18S substitution drastically reduces α-helices content of the metal-free and Mg2+-bound Ocm, increases solvent accessibility of its hydrophobic residues, eliminates the cooperative thermal transition in the apo-protein, suppresses Ca2+/Mg2+ affinity of the EF site, and accelerates Ca2+ dissociation from Ocm. The distinct structural and functional consequences of the minor structural modification of Cys18 indicate its possible redox sensory function. Since some other EF-hand proteins also contain a conservative redox-sensitive cysteine located in an inactive EF-hand loop, it is reasonable to suggest that in the course of evolution, some of the EF-hands attained redox sensitivity at the expense of the loss of their Ca2+ affinity.

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