Ion channel-kinase TRPM
            <i>7</i>
            is required for maintaining cardiac automaticity

Sah, Rajan; Mesirca, Pietro; Boogert, Marjolein Van den; Rosen, Jonathan N.; Mably, John D.; Mangoni, Matteo E.; Clapham, David E.

doi:10.1073/pnas.1311865110

Cited by 105 publications

(80 citation statements)

References 44 publications

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“…TRPM7 has also been implicated in cardiac regulation and growth, since disturbed TRPM7 activity leads to abnormal cardiogenesis and impaired ventricular function (36, 37). In rat cardiomyocytes increased TRPM7 activity was involved in Ang II-induced cardiac fibrosis (48).…”

Section: Discussionmentioning

confidence: 99%

“…In mouse heart and aorta, upregulation of TRPM7 channels by Ang II was associated with a proliferative phenotype of ascending aortic smooth muscle cells, an effect that was mediated through TRPM7 suppression of Pyk2-ERK1/2-Elk-1 signaling (49). Moreover cardiac arrhythmias have been linked to both up- and down-regulation of TRPM7 (35, 36). In our study, decreased TRPM7kinase activity was associated with exaggerated cardiac hypertrophy and pronounced left ventricular dysfunction in Ang II-infused mice.…”

Section: Discussionmentioning

confidence: 99%

“…In cells from TRPM7-knockout mice and in cells in which siRNA is targeted to TRPM7, growth is abnormal, proliferation is arrested and cells undergo apoptosis and death (11, 12). In embryonic cardiomyocytes in which TRPM7 is disrupted, spontaneous Ca 2+ transient firing is reduced with associated downregulation of voltage-dependent Ca 2+ channel (36). At the whole animal level, homozygous TRPM7 kinase (Δ kinase) knockout is embryonic lethal, indicating the critical role of TRPM7 kinase for normal development (11,12,37).…”

Section: Introductionmentioning

confidence: 99%

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Transient Receptor Potential Melastatin 7 Cation Channel Kinase

Antunes

Callera

et al. 2016

Hypertension

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Transient receptor potential melastatin 7 (TRPM7) is a bi-functional protein comprising a magnesium (Mg2+)/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7kinase-deficient mice (TRPM7Δkinase) (heterozygous for TRPM7kinase) and wildtype (WT) mice infused with Ang II (400 ng/kg/min, 4 weeks). TRPM7kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg2+ was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (p<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7Δkinase mice, an effect associated with Akt and eNOS downregulation. Vascular VCAM-1 expression was increased in Ang II-infused TRPM7kinase-deficient mice. TRPM7 kinase targets, calpain and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathological analysis demonstrated cardiac hypertrophy and LV dysfunction in Ang II-treated groups. In TRPM7kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Δkinase mice, Ang II-induced hypertension is exaggerated, cardiac remodelling and LV dysfunction are amplified and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7kinase expression/signaling, eNOS downregulation and pro-inflammatory vascular responses. Our findings identify TRPM7kinase as a novel player in Ang II-induced hypertension and associated vascular and target organ damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transient Receptor Potential Melastatin 7 Cation Channel Kinase

Antunes

Callera

et al. 2016

Hypertension

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“…A typical trace of an ECG shows the "P-wave", the "P-Q interval" (isoelectric line), the "QRS complex", the "T-wave" and the "U-wave". [60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75] in the SAN). This "SAN overdrive suppression" on the other elements of the conductive network explains its leading role in driving the pacemaker.…”

Section: Development Of the Human Cardiac Conduction Systemmentioning

confidence: 99%

“…Restricted TRPM7 deletion in the mouse SAN disrupts cardiac automaticity in vivo, leading to sinus pauses and an AV block. Molecularly, TRPM7 knockdown alters HCN4 expression, leading to its downregulation and subsequent changes in automaticity [73] . Inward-rectifier potassium currents, such as I KACh or I KATP , which are expressed in the SAN, can also modulate the DD slope.…”

Section: Wwwchinapharcom Weisbrod D Et Almentioning

confidence: 99%

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

et al. 2016

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The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cellderived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca 2+ -activated K + channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

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ProBDNF induces sustained elevation of intracellular Ca²⁺ possibly mediated by TRPM7 channels in rodent microglial cells

Mizoguchi

Ohgidani

Haraguchi

et al. 2021

Glia

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Microglia are intrinsic immune cells that release factors including pro‐ and anti‐inflammatory cytokines, nitric oxide (NO) and neurotrophins following activation in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+]i) is important for microglial functions, such as the release of cytokines or NO from activated microglia. Brain‐derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia. Interestingly, proBDNF, the precursor form of mature BDNF, and mature BDNF elicit opposing neuronal responses in the brain. Mature BDNF induces sustained intracellular Ca2+ elevation through the upregulation of the surface expression of TRPC3 channels in rodent microglial cells. In addition, TRPC3 channels are important for the BDNF‐induced suppression of NO production in activated microglia. In this study, we observed that proBDNF and mature BDNF have opposite effects on the relative expression of surface p75 neurotrophin receptor (p75NTR) in rodent microglial cells. ProBDNF induces a sustained elevation of [Ca2+]i through binding to the p75NTR, which is possibly mediated by Rac 1 activation and TRPM7 channels in rodent microglial cells. Flow cytometry showed that proBDNF increased the relative surface expression of TRPM7. Although proBDNF did not affect either mRNA expression of pro‐ and anti‐inflammatory cytokines or the phagocytic activity, proBDNF potentiates the generation of NO induced by IFN‐γ and TRPM7 channels could be involved in the proBDNF‐induced potentiation of IFN‐γ‐mediated production of NO. We show direct evidence that rodent microglial cells are able to respond to proBDNF, which might be important for the regulation of inflammatory responses in the brain.

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Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

Cited by 105 publications

References 44 publications

Transient Receptor Potential Melastatin 7 Cation Channel Kinase

Transient Receptor Potential Melastatin 7 Cation Channel Kinase

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

ProBDNF induces sustained elevation of intracellular Ca²⁺ possibly mediated by TRPM7 channels in rodent microglial cells

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Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

Cited by 105 publications

References 44 publications

Transient Receptor Potential Melastatin 7 Cation Channel Kinase

Transient Receptor Potential Melastatin 7 Cation Channel Kinase

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

ProBDNF induces sustained elevation of intracellular Ca2+ possibly mediated by TRPM7 channels in rodent microglial cells

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Product

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ProBDNF induces sustained elevation of intracellular Ca²⁺ possibly mediated by TRPM7 channels in rodent microglial cells