Regulation of Mg2+ Reabsorption and Transient Receptor Potential Melastatin Type 6 Activity by cAMP Signaling

Blanchard, Maxime; Kittikulsuth, Wararat; Nair, Anil V.; Baaij, Jeroen H. F. de; Latta, Femke; Genzen, Jonathan R.; Kohan, Donald E.; Bindels, René J. M.; Hoenderop, Joost G. J.

doi:10.1681/asn.2014121228

Cited by 24 publications

(25 citation statements)

References 52 publications

(80 reference statements)

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“…The mechanisms by which mutations in TRPM6 lead to HSH are unknown, although several studies stress the importance of TRPM6-mediated Mg 2+ conductance (3)(4)(5). Importantly, global TRPM6 disruption in mice is embryonic lethal (6,7).…”

Section: For a Recent Review)mentioning

confidence: 99%

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Krapivinsky

Renthal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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.A mong the several hundred genes encoding cation channels, the melastatin-related transient receptor potential family members TRPM6 and TRPM7 are unique in also being serine/ threonine (S/T) kinases (1). The TRPM6 channel kinase was brought to greater attention when mutations in this chanzyme were found to be the cause of familial hypomagnesemia with secondary hypocalcemia (HSH; see ref. 2 for a recent review). Characterized by severe hypomagnesemia, infants with HSH suffer tetany and refractory seizures shortly after birth, resulting in permanent neurological damage or death if untreated. The mechanisms by which mutations in TRPM6 lead to HSH are unknown, although several studies stress the importance of TRPM6-mediated Mg 2+ conductance (3-5). Importantly, global TRPM6 disruption in mice is embryonic lethal (6, 7). Mice with loss of TRPM6 at intermediate developmental time points manifest a reduced life span and skeletal deformations, in addition to mild hypomagnesemia (5). These data indicate that, much like TRPM7 (8), TRPM6 may be critical for normal, developmental, tissue-specific regulation of gene activity.Recently, our laboratory uncovered a signaling pathway mediated by TRPM7, a channel sharing 52% homology with TRPM6, whereby the functional S/T kinase at the carboxyl terminus of TRPM7 is proteolytically cleaved from the channel domain, forming cleaved kinase fragments (M7CKs) that translocate to the nucleus (9). There, M7CKs bind components of chromatin-remodeling complexes to ultimately phosphorylate specific S/T residues of histones, regulate selected histone acetylatio...

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Section: For a Recent Review)mentioning

confidence: 99%

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Krapivinsky

Renthal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies have shown that plasma membrane TRPM6 expression can be stimulated by the adenylyl cyclase 3 (AC3)/ cAMP/PKA-mediated signaling pathway. AC3 is also colocalized with Na-Cl cotransporter (NCC) in the DCL [49] . In mice with kidney-specific AC3 knockout, urine Mg 2+ wasting, hypomagnesemia when on a low-Mg 2+ diet, colocalization of AC3 and NCC, and activation of cAMP-PKA with increasing apical membrane expression and channel conductance of TRPM6 have all been demonstrated [49] .…”

Section: Trpm6mentioning

confidence: 99%

“…AC3 is also colocalized with Na-Cl cotransporter (NCC) in the DCL [49] . In mice with kidney-specific AC3 knockout, urine Mg 2+ wasting, hypomagnesemia when on a low-Mg 2+ diet, colocalization of AC3 and NCC, and activation of cAMP-PKA with increasing apical membrane expression and channel conductance of TRPM6 have all been demonstrated [49] . Schematic presentation of magnesium regulation in the distal convoluted tubule.…”

Section: Trpm6mentioning

confidence: 99%

“…The impairment of Na-K-ATPase function diminishes the driving force for apical NCC activity and compromises apical membrane voltage generation (partial depolarization of the cell), reducing the driving force for TRPM6-mediated Mg 2+ entry. Reduced NCC activity also compromises TRPM6 activation associated with AC3/cAMP/PKA signaling [49] .…”

Section: Gamma-subunit Of Na-k-atpasementioning

confidence: 99%

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Genetics of Magnesium Disorders

Sun

Chen

et al. 2017

Kidney Dis

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Background: Magnesium (Mg²⁺), the second most abundant cation in the cell, is woven into a multitude of cellular functions. Dysmagnesemia is associated with multiple diseases and, when severe, can be life-threatening. Summary: This review discusses Mg²⁺ homeostasis and function with specific focus on renal Mg²⁺ handling. Intrarenal channels and transporters related to Mg²⁺ absorption are discussed. Unraveling the rare genetic diseases with manifestations of dysmagnesemia has greatly increased our understanding of the complex and intricate regulatory network in the kidney, specifically, functions of tight junction proteins including claudin-14, -16, -19, and -10; apical ion channels including: TRPM6, K_v1.1, and ROMK; small regulatory proteins including AC3 and ANK3; and basolateral proteins including EGF receptor, γ-subunit (FXYD2) of Na-K-ATPase, K_ir4.1, CaSR, CNNM2, and SLC41A. Although our understanding of Mg²⁺ handling of the kidney has expanded considerably in the last two decades, many questions remain. Future studies are needed to elucidate a multitude of unknown aspects of Mg²⁺ handling in the kidney. Key Message: Understanding rare and genetic diseases of Mg²⁺ dysregulation has expanded our knowledge and furthers the development of strategies for preventing and managing dysmagnesemia.

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“…Consistently, cisplatin downregulates the EGF and TRPM6 mRNA levels and increases the fractional excretion Mg 2+ , suggesting that cisplatin treatment results in a diminished renal Mg 2+ reabsorption via TRPM6 [92]. Adenylyl Cyclase 3 (AC3)-PKA signaling pathway A also increases TRPM6 abundance at the apical plasma membrane and channel activity, but the upstream extracellular signal was not defined [93]. In addition to hormonal control, renal TRPM6 expression is under control of other systemic factors.…”

Section: Introductionmentioning

confidence: 99%

Role of renal TRP channels in physiology and pathology

et al. 2015

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Kidneys critically contribute to the maintenance of whole-body homeostasis by governing water and electrolyte balance, regulating extracellular fluid volume, plasma osmolality and blood pressure. Renal function is regulated by numerous systemic endocrine and local mechanical stimuli. Kidneys possess a complex network of membrane receptors, transporters and ion channels which allows responding to this wide array of signaling inputs in an integrative manner. Transient receptor potential (TRP) channel family members with diverse modes of activation, varied permeation properties and capability to integrate multiple downstream signals are pivotal molecular determinants of renal function all along the nephron. This review summarizes experimental data on the role of TRP channels in a healthy mammalian kidney and discusses their involvement in renal pathologies.

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Regulation of Mg2+ Reabsorption and Transient Receptor Potential Melastatin Type 6 Activity by cAMP Signaling

Cited by 24 publications

References 52 publications

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Genetics of Magnesium Disorders

Role of renal TRP channels in physiology and pathology

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