Dataset Information

The histone variant MacroH2A regulates Ca(2+) influx through TRPC3 and TRPC6 channels.

ABSTRACT: The histone variant macroH2A replaces canonical H2A in the designated region of chromatin where its incorporation has the potential to establish a functionally distinct chromatin domain. The transient receptor potential canonical (TRPC) channels are a family of Ca(2+)-permeable cationic channels controlling changes in the cytosolic Ca(2+) concentration. The proper regulation of Trpc gene expression requires chromatin remodeling, but little is known about the nature of these regulatory processes. Here, we show that macroH2A1 represses two Trpc family genes, Trpc3 and Trpc6, and attenuates Ca(2+)-dependent proliferative responses in bladder cancer cells. MacroH2A1 recruits histone deacetylase 1 (HDAC1) and HDAC2 to facilitate its persistent action, resulting in a compromise of histone acetylation across the Trpc3 and Trpc6 loci. Further, macroH2A1 depletion augments histone acetylation and Ca(2+) influx, leading to increased cell growth and invasion. Our data provide new insights into TRPC3/TRPC6-mediated Ca(2+) signaling and indicate a central role for macroH2A1 in regulating transcriptional competence of Trpc3 and Trpc6 genes.

SUBMITTER: Kim JM

PROVIDER: S-EPMC3816217 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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The histone variant MacroH2A regulates Ca(2+) influx through TRPC3 and TRPC6 channels.

Kim J-M JM Heo K K Choi J J Kim K K An W W

Oncogenesis 20131028

The histone variant macroH2A replaces canonical H2A in the designated region of chromatin where its incorporation has the potential to establish a functionally distinct chromatin domain. The transient receptor potential canonical (TRPC) channels are a family of Ca(2+)-permeable cationic channels controlling changes in the cytosolic Ca(2+) concentration. The proper regulation of Trpc gene expression requires chromatin remodeling, but little is known about the nature of these regulatory processes. ...[more]

PMID: 24165580

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Project description:BACKGROUND AND PURPOSE: The calcimimetic, (R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-napthyl)ethylamine hydrochloride (cinacalcet), which activates Ca²(+) -sensing receptors (CaR) in parathyroid glands, is used to treat hyperparathyroidism. Interestingly, CaR in perivascular nerves or endothelial cells is also thought to modulate vascular tone. This study aims to characterize the vascular actions of calcimimetics. EXPERIMENTAL APPROACH: In rat isolated small mesenteric arteries, the relaxant responses to the calcimimetics, cinacalcet and (R)-2-[[[1-(1-naphthyl)ethyl]amino]methyl]-1H-indole hydrochloride (calindol) were characterized, with particular emphasis on the role of CaR, endothelium, perivascular nerves, K(+) channels and Ca²(+) channels. Effects of L-ornithine, which activates a Ca(2+) -sensitive receptor related to CaR (GPRC6A), were also tested. KEY RESULTS: Cinacalcet induced endothelium-independent relaxation (pEC?? 5.58 ± 0.07, E(max) 97 ± 6%) that was insensitive to sensory nerve desensitization by capsaicin or blockade of large-conductance Ca²(+) -activated K(+) channels by iberiotoxin. Calindol, another calcimimetic, caused more potent relaxation (pEC?? 6.10 ± 0.10, E(max) 101 ± 6%), which was attenuated by endothelial removal or capsaicin, but not iberiotoxin. The negative modulator of CaR, calhex 231 or changes in [Ca²(+) ](o) had negligible effect on relaxation to both calcimimetics. The calcimimetics relaxed vessels precontracted with high [K(+) ](o) and inhibited Ca²(+) influx in endothelium-denuded vessels stimulated by methoxamine, but not ionomycin. They also inhibited contractions to the L-type Ca²(+) channel activator, BayK8644. L-ornithine induced small relaxation alone and had no effect on the responses to calcimimetics. CONCLUSION AND IMPLICATIONS: Cinacalcet and calindol are potent arterial relaxants. Under the experimental conditions used, they predominantly act by inhibiting Ca²(+) influx through L-type Ca²(+) channels into vascular smooth muscle, whereas Ca²(+) -sensitive receptors (CaR or GPRC6A) play a minor role.

Dataset Information

The histone variant MacroH2A regulates Ca(2+) influx through TRPC3 and TRPC6 channels.

Publications

The histone variant MacroH2A regulates Ca(2+) influx through TRPC3 and TRPC6 channels.

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