Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca<sup>2+</sup> signaling in mouse fibroblasts and neuronal cells via store-operated Ca<sup>2+</sup> entry pathway

Linde, Cristina I.; Feng, Bo; Wang, Jia Bei; Golovina, Vera A.

doi:10.1152/ajpcell.00073.2013

Cited by 7 publications

(6 citation statements)

References 53 publications

(76 reference statements)

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“…In vitro, HINT1 is a promiscuous enzyme, hydrolyzing diverse AMP-linked substrates [ 3 ] and acts as a SUMO1-cleaving Cys-protease [ 4 ], yet its endogenous substrate(s) remain unknown. HINT1 has been attributed pleiotropic cellular roles, including regulation of transcription factors involved in tumor progression and apoptosis [ 5 , 6 ], modulating G-protein coupled receptor signaling [ 7 ], and controlling calcium signaling via the store-operated calcium entry pathway [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

Malcorps

Amor-Barris

Burnytė

et al. 2022

Orphanet J Rare Dis

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Background Recessive loss-of-function variations in HINT1 cause a peculiar subtype of Charcot-Marie-Tooth disease: neuromyotonia and axonal neuropathy (NMAN; OMIM[#137200]). With 25 causal variants identified worldwide, HINT1 mutations are among the most common causes of recessive neuropathy. The majority of patients are compound heterozygous or homozygous for a Slavic founder variant (c.110G>C, p.Arg37Pro) that has spread throughout Eurasia and America. Results In a cohort of 46 genetically unresolved Lithuanian patients with suspected inherited neuropathy, we identified eight families with HINT1 biallelic variations. Most patients displayed sensorimotor or motor-predominant axonal polyneuropathy and were homozygous for the p.Arg37Pro variant. However, in three families we identified a novel variant (c.299A>G, p.Glu100Gly). The same variant was also found in an American patient with distal hereditary motor neuropathy in compound heterozygous state (p.Arg37Pro/p.Glu100Gly). Haplotype analysis demonstrated a shared chromosomal region of 1.9 Mb between all p.Glu100Gly carriers, suggesting a founder effect. Functional characterization showed that the p.Glu100Gly variant renders a catalytically active enzyme, yet highly unstable in patient cells, thus supporting a loss-of-function mechanism. Conclusion Our findings broaden NMAN’s genetic epidemiology and have implications for the molecular diagnostics of inherited neuropathies in the Baltic region and beyond. Moreover, we provide mechanistic insights allowing patient stratification for future treatment strategies.

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Section: Introductionmentioning

confidence: 99%

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

Malcorps

Amor-Barris

Burnytė

et al. 2022

Orphanet J Rare Dis

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“…We present a focused look at expression in the central nervous system (CNS) across nonclinical species. Previous reports using antibodies directed at the C-terminus of ORAI1 have not detected CNS expression by immunohistochemistry (IHC) in mouse or human tissues (Gwack et al 2008;McCarl et al 2009), although there has been one published report of CNS expression using western blotting of mouse brain extracts (Linde et al 2013). We also present in situ hybridization (ISH) results using a probe directed to the middle of the RNA transcript for mouse Orai1 where CNS expression is also detected.…”

Section: Introductionmentioning

confidence: 99%

Expression of ORAI1, a Plasma Membrane Resident Subunit of the CRAC Channel, in Rodent and Non-rodent Species

Guzman

Valente

Pretorius

et al. 2014

J Histochem Cytochem.

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SummaryWe determined the expression of ORAI1 protein in rodent and non-rodent tissues using a monoclonal antibody directed against an extracellular loop of the protein. Previous reports using antibodies directed at the C-terminus of ORAI1 have not detected central nervous system (CNS) expression. Our results demonstrate broad tissue expression that includes the CNS using a unique monoclonal antibody specific to an extracellular loop of ORAI1. In addition, we present in situ hybridization (ISH) results using a probe within the middle of the mouse coding region showing CNS expression of Orai1 RNA. We contrast the patterns of rodent and human tissue expression and conclude that rodents have similar expression of ORAI1 in most tissue types when compared to primates, with an important exception being the male reproductive system, where human-specific expression is observed. (J Histochem Cytochem 62:864-878, 2014)

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“…HINT1 is implicated as a tumor suppressor; consistent with that, haplo-insufficiency results in increased tumor incidence (7, 8). HINT1 also interacts with intracellular signaling pathways, such as regulation of store-operated calcium levels and a direct interaction with Microphthalmia-associated transcription factor (MITF) (9, 10). The HINT1-MITF interaction is regulated by diadenosine tetraphosphate (AP4A), which is produced as a side reaction of tRNA synthetases, and HINT1 enzymatic activity may influence AP4A levels, thereby providing a mechanism for self-regulation (11).…”

Section: Introductionmentioning

confidence: 99%

Lack of Neuropathy-Related Phenotypes inHint1Knockout Mice

Seburn

Morelli

Jordanova

et al. 2014

J Neuropathol Exp Neurol

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Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that involves primarily motor dysfunction and is usually associated with neuromyotonia, i.e. prolonged muscle contraction resulting from hyperexcitability of the peripheral nerve. Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 were normal in appearance and in behavioral tests or motor performance, although they moved slower and for a smaller fraction of time than wild-type (WT) mice in an open field arena. Muscles, neuromuscular junctions, and nodes of Ranvier are anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at 4 and 13 months of age. Axons were slightly smaller than those in WT mice at 4 months of age, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. Using electromyography, we were unable to detect neuromyotonia, even using supra-physiological stimuli and stressors such as reduced temperature or 3,4 diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia.

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Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca²⁺ signaling in mouse fibroblasts and neuronal cells via store-operated Ca²⁺ entry pathway

Cited by 7 publications

References 53 publications

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

Expression of ORAI1, a Plasma Membrane Resident Subunit of the CRAC Channel, in Rodent and Non-rodent Species

Lack of Neuropathy-Related Phenotypes inHint1Knockout Mice

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Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca2+ signaling in mouse fibroblasts and neuronal cells via store-operated Ca2+ entry pathway

Cited by 7 publications

References 53 publications

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling

Expression of ORAI1, a Plasma Membrane Resident Subunit of the CRAC Channel, in Rodent and Non-rodent Species

Lack of Neuropathy-Related Phenotypes inHint1Knockout Mice

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Histidine triad nucleotide-binding protein 1 (HINT1) regulates Ca²⁺ signaling in mouse fibroblasts and neuronal cells via store-operated Ca²⁺ entry pathway