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Grigory Krapivinsky - One of the best experts on this subject based on the ideXlab platform.
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Histone Phosphorylation by trpm6 s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Ana Santacruz, Yunona Manasian, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
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Histone Phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Yunona Manasian, Ana Santa-cruz, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
David E Clapham - One of the best experts on this subject based on the ideXlab platform.
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Histone Phosphorylation by trpm6 s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Ana Santacruz, Yunona Manasian, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
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Histone Phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Yunona Manasian, Ana Santa-cruz, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
David J Sweatt - One of the best experts on this subject based on the ideXlab platform.
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erk mapk regulates hippocampal Histone Phosphorylation following contextual fear conditioning
Learning & Memory, 2006Co-Authors: Wilson B Chwang, Kenneth J Oriordan, Jonathan M Levenson, David J SweattAbstract:Long-term memory formation is a complex process involving biochemical signaling cascades that lead to a change in gene expression in neurons. In mammalian associative memory tasks, activation of the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) cascade in the hippocampus is necessary for consolidation of the memory (Atkins et al. 1998). This is accomplished typically by activation of the NMDA (N-methyl-d-aspartic acid) subtype of glutamate receptors, leading to an increase in intracellular Ca2+ (Fanselow et al. 1994). Ca2+ activates Ca2+-sensitive protein kinase C (PKC) and adenylyl cyclase/protein kinase A (PKA), triggering a series of events that eventually converge upon ERK (Adams and Sweatt 2002). Once activated, ERK translocates into the nucleus to coordinate and effect changes in gene expression (Davis et al. 2000). ERK is known to regulate transcription factors such as CREB (Cre-binding protein) and Elk-1 (Sweatt 2001), which help initiate transcription of memory-associated genes that contain their respective regulatory elements. There is growing evidence that memory formation also utilizes epigenetic mechanisms that modify the structure of chromatin (Swank and Sweatt 2001; Guan et al. 2002; Alarcon et al. 2004; Korzus et al. 2004; Wood et al. 2005; for review, see Levenson and Sweatt 2005). Epigenetic modifications can serve as enduring changes to the epigenome that help drive stable changes in gene expression (Rakyan et al. 2001), which in turn manifest as a long-lasting change in behavior. Mechanistically, this is accomplished by direct modification of DNA or post-translational modification of Histone proteins, including methylation, acetylation, and Phosphorylation (Berger 2002). These modifications exert their effects either by physical remodeling of chromatin structure or by further recruitment of signaling complexes that drive or repress transcription. In addition, epigenetic marks themselves constitute a form of cellular memory. Cellular storage and propagation of information is critical in processes such as mitosis and differentiation, during which patterns of gene expression are preserved and transmitted as unique traits of a particular cell (Ehrenhofer-Murray 2004). Although adult neurons are terminally differentiated and no longer divide, recent studies indicate that epigenetic mechanisms may come into play to subserve information storage in the adult nervous system as well (Guan et al. 2002; Alarcon et al. 2004; Korzus et al. 2004; Levenson et al. 2004b; Wood et al. 2005). Regulation of Histone modifications has been observed in neurons with a variety of physiological stimuli. Exposure of animals to light pulses resulted in transient changes in Histone Phosphorylation in neurons of the suprachiasmatic nucleus (Crosio et al. 2000). Neuronal stimulation by several neurotransmitter signaling pathways induced changes in Histone Phosphorylation and acetylation, and also resulted in immediate-early gene (IEG) expression (Crosio et al. 2003). Also, boosting Histone acetylation levels in the hippocampus was found to enhance long-term potentiation, a physiological correlate of learning (Levenson et al. 2004b), and disruption of the CREB-binding protein CBP, a known transcriptional activator and Histone acetyltransferase, was found to impair both memory consolidation and long-term potentiation in the hippocampus (Alarcon et al. 2004; Korzus et al. 2004). All of these studies suggest that chromatin is a highly dynamic structure in the nervous system that is modified in response to various environmental signals. Histone Phosphorylation has been implicated as a target of the ERK/MAPK pathway. The kinases MSK1 and MSK2 (mitogen- and stress-activated protein kinase), which are downstream of ERK, mediate the mitogen- and stress-induced Phosphorylation of Histone H3 in cell culture systems in vitro (Soloaga et al. 2003). Levels of Histone H3 Phosphorylation were significantly diminished in knockout cells for MSK1 and MSK2, and this deficiency was partially rescued by transfection of GFP-tagged MSK2 (Soloaga et al. 2003). Oncogene-transformed fibroblasts, in which the Ras-MAPK pathway is constitutively active, show an increase in Histone H1 and H3 Phosphorylation and have relaxed chromatin structure (Dunn et al. 2005). Also, when activated by ERK, MSK phosphorylates Histone H3 and is required for transcription of nuclear orphan receptors in cultured fibroblasts (Darragh et al. 2005). Interestingly, the same Phosphorylation site on Histone H3 is used as a marker for dividing chromosomes in mitosis (Hendzel et al. 1997), indicating that a single Histone modification may have disparate functions within the cell depending on its context (Jenuwein and Allis 2001). Given the importance of ERK in mammalian associative learning and the importance of Histone Phosphorylation in regulating gene expression, we investigated whether ERK regulates Histone Phosphorylation in CA1 hippocampal neurons during long-term memory formation. We report that activation of ERK in hippocampal slices in vitro, using activators of PKA and PKC, resulted in a significant increase in Histone H3 Phosphorylation. We then turned to the behaving animal to assess Histone H3 Phosphorylation with contextual fear conditioning, a robust model of associative learning. H3 Phosphorylation was regulated by this paradigm in a time-dependent manner, peaking at 1 h after training before returning to baseline. This effect also required the activation of NMDA receptors and was blocked by a latent inhibition training paradigm. Finally, the increases in Histone H3 Phosphorylation in the fear-conditioned animal were reduced by inhibition of MAP kinase/ERK kinase (MEK), the kinase upstream of ERK, after training. These results demonstrate that Phosphorylation of Histone H3 at serine 10 (Ser10) is regulated by an ERK-dependent process in long-term memory.
Yunona Manasian - One of the best experts on this subject based on the ideXlab platform.
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Histone Phosphorylation by trpm6 s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Ana Santacruz, Yunona Manasian, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
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Histone Phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Yunona Manasian, Ana Santa-cruz, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
Luba Krapivinsky - One of the best experts on this subject based on the ideXlab platform.
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Histone Phosphorylation by trpm6 s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Ana Santacruz, Yunona Manasian, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.
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Histone Phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Grigory Krapivinsky, Luba Krapivinsky, Nora E Renthal, Yunona Manasian, Ana Santa-cruz, David E ClaphamAbstract:TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific Histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating Histone arginine residues. Histone Phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in Histone S/T Phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific Histone Phosphorylation. M6CK Histone Phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.