Obesity-diabetes syndrome poses a considerable risk for mild cognitive impairment (MCI). Our study was designed to explore therapeutic potential of u03B3-oryzanol (Orz), a brown rice-specific oil composed of ferulic acid ester with several phytosterols, on MCI in high-fat diet (HFD) induced obese aged mice. After being housed on an HFD for 4 months, regular Orz or the nanoparticulated form of Orz (Nano-Orz), which markedly enhances its intestinal absorption, was administered to aged mice. Mice treated with regular Orz for 4 months exhibited significant improvement in spatial cognitive function. Impressively, mice treated with Nano-Orz demonstrated cognitive improvement as early as 1 month, with substantial recovery by 3 months. In the hippocampus, treatment with both regular Orz and Nano-Orz upregulated genes associated with neurogenesis and stem cell function accompanied by a significant increase in gene expressions of anti-inflammatory cytokines. Our data highlight a therapeutic potential of Orz for obesity-associated MCI.

Summary Human pluripotent stem cells (hPSCs) rely on glycolysis and exhibit low mitochondrial respiration, conditions under which F1Fo ATP synthase tends to run in reverse, hydrolyzing ATP. ATP synthase inhibitory factor subunit 1 (IF1) inhibits F1Fo-mediated ATP hydrolysis, but its significance in glycolytic hPSCs remains unclear. Here, we show that stable IF1 knockdown (IF1-KD) in human induced pluripotent stem cells (hiPSCs) enhanced mitochondrial ATP hydrolysis and elevated the mitochondrial membrane potential (ΔΨm). Markers of the undifferentiated state were largely maintained, whereas IF1-KD cells exhibited reduced epithelial characteristics and a partial epithelial-mesenchymal transition (EMT)-like state. IF1-KD cells also showed enhanced store-operated Ca²⁺ entry (SOCE) and increased nuclear NFATc3. Pharmacological reduction of ΔΨm attenuated SOCE, whereas NFATc3 overexpression reproduced key features of the EMT-like expression pattern. Endogenous IF1 therefore acts as a constitutive restraint on reverse-mode F1Fo activity, limiting excessive ΔΨm and downstream SOCE–NFATc3 signaling and safeguarding the epithelial state of hPSCs. Graphical Abstract

Background: Ischemic heart disease is one of the leading causes of death worldwide. Timely reperfusion is necessary for myocardium salvage but triggers paradoxical cardiomyocyte death and contributes to up to 50% of the final infarct size, known as lethal ischemia/reperfusion (I/R) injury. TRPM7 (transient receptor potential melastatin 7) is a divalent cation-permeable, nonselective channel kinase that can sense oxidative stress and release Zn2+ from unique intracellular TRPM7 vesicles. However, the pathophysiological role of intracellular TRPM7 remains poorly understood. Methods: TRPM7 expression was determined in hearts from patients with ischemic heart failure and I/R-injured mice. Global (gTrpm7(-/-)), cardiomyocyte-specific (cmTrpm7(-/-)), and fibroblast-specific (fibTrpm7(-/-)) Trpm7 knockout mice were used to determine the role of TRPM7 in I/R injury. Mechanistic investigations were conducted in neonatal and adult mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with patch-clamp, Zn-2(+) imaging, and molecular biology techniques. An inducible TRPM7 channel-dead (TRPM7-E1047K) knock-in mouse model was generated to elucidate the functional domains of TRPM7 for therapeutic strategies. Results: We found that TRPM7 was significantly upregulated in myocardium from both patients with ischemic heart failure and I/R-injured mice. Global TRPM7 deficiency markedly reduced infarct size and improved cardiac function after I/R injury. Using cmTrpm7(-/-) and fibTrpm7(-/-) mice, we demonstrated that TRPM7 deficiency in myocytes, rather than in fibroblasts, confers protection against I/R injury by inhibiting pyroptosis as evaluated. Furthermore, using mouse cardiomyocytes and hiPSC-CMs, we revealed that Zn2+ release from intracellular TRPM7 vesicles during I/R injury triggers cardiomyocyte death by activating gasdermin-D to release its N-terminal and form the membrane pore. The critical role of intracellular TRPM7 was further supported by the inability of membrane TRPM7 inhibition to protect mice against I/R injury. To elucidate whether the channel or kinase activity of TRPM7 mediates pyroptosis in I/R injury, we generated an inducible channel-dead TRPM7-E1047K knock-in mouse model. By comparing with kinase-inactive TRPM7 knock-in mice, we uncovered that the channel but not the kinase function of TRPM7 mediates I/R injury. Conclusions: TRPM7-mediated intracellular Zn-2(+) release contributes to myocardial I/R injury by triggering apoptotic and pyroptotic cardiomyocyte death. Given that TRPM7 is highly upregulated in patients with ischemic heart failure, our findings suggest that targeting TRPM7 may represent a novel therapeutic strategy for ischemic heart disease.

Muscle satellite cells (MuSCs) respond immediately to environmental cues upon skeletal muscle injuries. Despite decades of research into muscle regeneration, the specific molecular factors that trigger the transition of MuSCs from a quiescent to an active state remain largely unidentified. Here, we identify transient receptor potential melastatin 7 (TRPM7), an Mg2+-permeable ion channel, as a critical regulator of MuSC activation. Trpm7 deletion in MuSCs reduced Mg2+ influx, impairing myofiber regeneration and leading to decreased MuSC numbers and cell cycle arrest during regeneration. These changes were linked to disrupted mTOR signaling, which drives the transition of MuSCs from G0 to GAlert phase. In addition, Trpm7-deficient MuSCs exhibited impaired early responses, including quiescent projection retraction and AP-1 induction. Mg2+ supplementation rescued these defects, restoring normal MuSC activation. Our findings reveal a previously unrecognized mechanism where Mg2+ permeation through TRPM7 is essential for MuSC activation and efficient skeletal muscle regeneration, highlighting TRPM7 as a critical regulator of muscle repair.

Abdominal aortic aneurysms (AAAs) occur in 1-2% of the elderly. The rupture of an AAA usually causes uncontrollable lethal hemorrhage, and its risk increases with AAA size. However, there is no effective pharmacological therapy for hindering AAA growth. Here we show that global or vascular smooth muscle cell (VSMC)-specific transient receptor potential melastatin 7 (TRPM7) knockout in mice prevented AAA formation, as indicated by inhibited VSMC reprogramming, reduced inflammatory infiltration and suppressed matrix degradation. Mechanistically, we showed that TRPM7-mediated Ca2+ signaling promotes Kruppel-like factor 4 (KLF4) activation, driving VSMC reprogramming and accelerating AAA growth. By generating channel-dead and using kinase-inactive knockin mice, we found that it is the channel function, rather than kinase activity, that is required for TRPM7-mediated AAA pathogenesis. Importantly, TRPM7 inhibitor NS8593 suppressed VSMC reprogramming and protected mice against AAA formation. Our data suggest that TRPM7 is a promising therapeutic target for developing effective prophylactic medications to limit AAA progression. In addition, the channel-dead TRPM7 knockin mice will serve as a valuable tool for elucidating the roles of TRPM7 in other pathophysiological conditions.

Aim: The present cohort study explored whether specific gut microbiota (GM) profile would predict the development of impaired glucose tolerance (IGT) in individuals with normal glucose tolerance (NGT). Methods: A total of 114 study subjects with NGT in Kumejima island, Japan participated in the present study and underwent 75 g oral glucose tolerance tests at baseline and one year later. We compared the profile of GM at baseline between individuals who consistently maintained NGT (NRN, n = 108) and those who transitioned from NGT to IGT (NTI, n = 6). Results: Within-individual bacterial richness and evenness as well as inter-individual bacterial composition showed no significant differences between NRN and NTI. Of note, however, partial least squares discriminant analyses revealed distinct compositions of GM between groups, with no overlap in their 95 % confidence interval ellipses. Multi-factor analyses at the genus level demonstrated that the proportions of CF231, Corynebacterium, Succinivibrio, and Geobacillus were significantly elevated in NTI compared to NRN (p < 0.005, FDR < 0.1, respectively) after adjusting for age, sex, HbA1c level, and BMI. Conclusions: Our data suggest that increased proportion of specific GM is linked to the future deterioration of glucose tolerance, thereby serving as a promising predictive marker for type 2 diabetes mellitus.

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Transient receptor potential melastatin-subfamily member 7 (TRPM7) is a bifunctional protein containing a kinase fused to an ion channel permeated with cations, including Ca2+ and Mg2+. Trpm7-null mice show embryonic lethality. Paired related homeobox 1 (Prx1) is expressed in undifferentiated mesenchymal cells such as the progenitor cells of both chondrocytes and osteoblasts involved in limb skeleton formation. Prx1-Cre-dependent Trpm7 mesenchymal-deleted mice were generated to examine the role of TRPM7 in bone development. We found that Prx1-Cre;Trpm7fl/fl mice had shortened bones and impaired trabecular bone formation. Trabecular bone parameters, such as the bone volume (BV/TV), and trabecular number (Tb.N), were decreased in Prx1-Cre;Trpm7fl/fl mice. The cortical bone parameters of cortical bone area (Ct.Ar) and cortical bone thickness (Ct.Th) were also down-regulated in these mice. The bone formation rate in Prx1-Cre;Trpm7fl/fl mice was unchanged, but the hypertrophic area and cell size of the zone were smaller, and the expression of Col2a1, Col10a1 and Mmp13 was downregulated compared with control mice. These findings suggest impaired chondrogenesis in Prx1-Cre;Trpm7fl/fl mice compared to control mice. The receptor activator of nuclear factor-kappa B ligand (RANKL) expression was increased, and RANKL-positive cells and osteoclasts were markedly accumulated in the boundary region between the growth plate and trabecular bone. In contrast, TRPM7 KR mice, which are kinase-dead mutants in which the TRPM7 ion channel function has not been altered, showed no marked differences in trabecular or cortical bone parameters compared to wild-type mice. These findings suggest that TRPM7 is critical as a cation channel rather than as a kinase in bone development via the regulation of chondrogenesis.

Under the dysfunction of mitochondria, cancer cells preferentially utilize both glycolytic and pentose phosphate pathways rather than electron transport chains to desperately generate adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH), classically recognized as the Warburg effect. Based on this background, the present study tested the hypothesis that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors would exert a tumor-suppressive impact on intractable human hematological malignancies via the modulation of glucose metabolism within cells and cell cycles. The level of mRNA for SGLT2 was remarkably elevated in leukemic cells from patients with adult T-cell leukemia (ATL), one of the most intractable blood cancers in humans, and as well as in two kinds of ATL cell lines (MT-1 and MT-2). Two kinds of SGLT2 inhibitors, Luseogliflozin and Tofogliflozin substantially suppressed the proliferation of MT-1 and MT-2 cells in both adherent and anchorage-independent culture conditions. Such a suppressive effect on tumor cell growth was reproduced by Luseogliflozin in leukemic cells in peripheral blood from patients with ATL. In MT-2 cells, both of SGLT2 inhibitors considerably attenuated glucose uptake, intracellular ATP levels, and NADPH production, resultantly enhancing cell cycle arrest at the G0/G1 phase. From the standpoint of metabolic oncology, the present study suggests that SGLT2 inhibitors would be a promising adjunctive option for the treatment of the most intractable human hematological malignancies like ATL.

Transient receptor potential melastatin 7 (TRPM7) is a unique protein that is both an ion channel and a cytosolic protein kinase. Normally, TRPM7 channels are tonically inhibited by cytoplasmic Mg2+, polyamines and acidic pH. Channel basal activity can be increased by alkalinization or Mg2+ depletion. We have used the TRPM7 kinase-dead (KD K1646R) mouse to investigate the consequences of kinase inactivation in immune cell function. It also serves as a convenient system to elucidate kinase-channel interactions at a functional level. CD4 and CD8 T lymphocytes isolated from the spleens of TRPM7 KD mice have defects in blastogenesis, proliferation and reduced store-operated calcium entry (SOCE) without a change in TRPM7 current magnitudes. Here we have investigated the effect of kinase inactivation in peritoneal and splenic macrophages. We examined phagocytosis using multiple approaches, finding that KD splenic macrophages phagocytize latex beads, zymosan particles and opsonized red blood cells more efficiently compared to WT. We observed somewhat higher basal cytosolic Ca2+ levels in KD macrophages compared to WT, but no differences in SOCE were apparent. Addition of calcium ionophore ionomycin overnight did not affect phagocytosis rates. By contrast, we found that cytosolic pH was alkalinized in KD mouse cells. In order to test if the KD effects on phagocytosis and pH were linked, we incubated the macrophages in presence of sodium-hydrogen exchanger 1 (NHE1) blockers and found that both pH and phagocytosis returned to normal, WT, levels. Moreover, the basal TRPM7 channel activity (current magnitude at break-in) was also reduced. WT and KD channel sensitivity to Mg2+ was similar. In summary, we have identified a new role for TRPM7 kinase as a regulator of cellular pH and phagocytosis.

Our recent study demonstrated the generation of induced tissue-specific stem/ progenitor (iTS/iTP) cells by the transient overexpression of reprogramming factors combined with tissue-specific selection. Here, we present a protocol to reprogram human hepatocytes to generate human induced tissue-specific liver stem (iTS-L) cells. Human hepatocytes are transfected with Sendai virus vectors (SeV) expressing OCT3/4, SOX2, KLF4, and c-MYC. iTS-L cells continuously express mRNA of hepatocyte-specific markers (HNF1b and HNF4a) and do not form teratomas. For complete details on the use and execution of this protocol, please refer to Nakashima et al. (2022).1

Numerous studies have revealed distinct differences in the profiles of gut microbiota between non-obese and obese individuals. To date, however, little is known if any disparities in the community of gut microbiota exist between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) subjects. We therefore aimed to comprehensively characterize the gut microbiota and circulating metabolites in serum from both MHO and MUO residing in the remote island, Kumejima, where the prevalence of obesity is one of the highest in Japan, and explored possible correlations between the gut microbiota profile and markers of metabolic syndrome. Results revealed that MUO showed significantly higher levels of genera such as g_Succinivibrio, g_Granulicatella, g_Brachyspira, g_Oribacterium and g_Atopobium in comparison to MHO. Moreover, abundance of g_Succinivibrio, g_Brachyspira and g_Atopobium were positively correlated with value of fasting insulin, HOMA-R, circulating triglycerides, diastolic blood pressure, BMI, body weight, waist circumference and HbA1c. In addition, MUO compared to MHO showed an imbalance of serum metabolites, with a significant elevation in 2-oxoisovaleric acid, pyruvic acid, 2-hydroxybutyric acid, and creatine. Our data highlight unmet needs in precision approaches for the treatment of obesity, targeting the gut microbiota profile and serum metabolites in a distinct population affected by obesity.

(1) Background: Evidence has accumulated regarding the etiology of lower urinary tract symptoms associated with obesity and metabolic syndrome. Therefore, the present study aimed to identify which subjectively and objectively measured voiding parameters were associated with obesity in a community-based population. (2) Methods: Voiding parameters on a self-administered questionnaire and a digital self-health monitoring system for urine excretion (s-HMSU) were compared between participants with and without obesity, defined as a body mass index ≥ 25 kg/m2 (n = 30 and 29, respectively), from a community in Okinawa, Japan. Logistic regression analysis was employed to calculate the odds ratios of abnormalities in voiding parameters for the obese group, with the non-obese group serving as a reference. (3) Results: The obese group had odds ratios of 5.17 (95% confidence interval: 1.33–20.0) for shortened hours of undisturbed sleep (<302 min) by s-HMSU and 7.65 (1.88–31.1) for nighttime urinary frequency by a questionnaire after adjusting for age and sex. In addition, the obese group had an adjusted odds ratio of 2.27 (0.76–6.78) for decreased maximum bladder capacity (<212 mL) by s-HMSU. (4) Conclusion: the results of the present study suggest that nocturia and shortened hours of undisturbed sleep are signs of obesity.

Human hepatocytes were transfected with Sendai virus vectors (SeV) expressing OCT3/4, SOX2, KLF4, and C-MYC to produce hepatocyte-derived induced pluripotent stem cells (iPSCs). The messenger RNA (mRNA) expression of undifferentiated markers (passage 19-21) and hepatocyte-specific markers (HSMs) (passage 0-20) in 48 established hepatocyte-derived iPSC-like colonies was examined. Among the 48 clones, 10 clones continuously expressed HSM mRNA (HNF1β and HNF4α) in passage 0-20. The colonies which expressed HSMs (iTS-L cells: induced tissue-specific stem cells from liver) showed a different tendency in microarray and methylation analyses to fibroblast-derived iPSCs (strain: 201B7). iTS-L cells were less likely to form teratomas in mice than iPSCs (He). The iTS-L cells were differentiated into hepatocyte-like cells more efficiently than iPSCs (He) or iPSCs (201B7). These data suggest that SeV expressing OCT3/4, SOX2, KLF4, and C-MYC induce the generation of iPSCs and iTS-L cells.

Induced pluripotent stem cells (iPSCs) obtained from genetically characterized patients benefit the biological study of bipolar disorder (BD). Here, we present iPSC lines from three-generation patients with BD and recurrent depressive disorder (RDD) and a healthy control sibling in a family. All patients shared the specified haplotype in the 1p36–35, previously reported as the susceptibility locus of mood disorders. iPSCs were generated with the reprogramming factors OTC3/4, l-MYC, LIN28, SOX2, KLF4, and p53 shRNA through non-integrated episomal vectors. All iPSC lines strongly expressed pluripotency markers and proved the ability to differentiate into three germ lineages in vitro.

Background: The etiology of bipolar disorder (BD) is poorly understood. Considering the complexity of BD, pedigree-based sequencing studies focusing on haplotypes at specific loci may be practical to discover high impact risk variants. This study comprehensively examined the haplotype sequence at 1p36-35 BD and recurrent depressive disorder (RDD) susceptibility loci. Methods: We surveyed BD families in Okinawa, Japan. We performed linkage analysis and determined the phased sequence of the affected haplotype using whole genome sequencing. We filtered rare missense variants on the haplotype. For validation, we conducted a case-control genetic association study on approximately 3000 Japanese subjects. Results: We identified a three-generation multiplex pedigree with BD and RDD. Strikingly, we identified a significant linkage with mood disorders (logarithm of odds [LOD] = 3.61) at 1p36-35, supported in other ancestry studies. Finally, we determined the entire sequence of the 6.4-Mb haplotype shared by all affected subjects. Moreover, we found a rare triplet of missense variants in the SPOCD1 gene on the haplotype. Notably, despite the rare frequency, one heterozygote with multiple SPOCD1 variants was identified in an independent set of 88 BD type I genotyping samples. Limitations: The 1p36-35 sequence was obtained from only a single pedigree. The replicate sample was small. Short-read sequencing might miss structural variants. A polygenic risk score was not analyzed. Conclusion: The 1p36-35 haplotype sequence may be valuable for future BD variant studies. In particular, SPOCD1 is a promising candidate gene and should be validated.

To evaluate the effect of a mobile digital intervention on voiding patterns, we performed 24-h voided volume monitoring in individuals with metabolic disorders. Participants with metabolic disorders were grouped into either the intervention group (n = 17), who had access to a smartphone app (CARADA), or the non-intervention group (n = 11), who did not. Urine monitoring was conducted for 24 h using a novel digital self-health monitoring system for urine excretion (s-HMSU). Body weight, abdominal circumference, blood pressure, and biomarkers were measured. Physical findings and blood test results at baseline and 6 months indicated no significant between-group differences. Night-time frequency did not change between baseline and 6 months in the intervention group but significantly worsened at 6 months in the non-intervention group, as compared to baseline (1.0 ± 0.7 vs. 1.5 ± 0.5, p < 0.05). The change in night-time frequency over 6 months did not differ between the intervention and non-intervention groups. Furthermore, the change in hours of undisturbed sleep over 6 months did not differ between the two groups. However, compared with baseline, nocturnal polyuria index tended to worsen at 6 months in the non-intervention group. Our study results suggest that mobile digital intervention might be useful for behavioral therapy to improve night-time frequency and urine production and that s-HMSU might be beneficial for confirming the prevention of progress in individuals with metabolic disorders, which can aid in modifying lifestyle.

During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. The transient-receptor-potential channel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion.

Several variant proteins are produced from EEF1D, including two representative proteins produced via alternative splicing machinery. One protein is the canonical translation eukaryotic elongation factor eEF1Bδ1, and the other is the heat shock-responsive transcription factor eEF1BδL. eEF1Bδ1 is phosphorylated by cyclin-dependent kinase 1 (CDK1), but the machinery controlling eEF1BδL phosphorylation and dephosphorylation has not been clarified. In this study, we found that both proteins were dephosphorylated under heat shock and proteotoxic stress, and this dephosphorylation was inhibited by okadaic acid. Using proteins with mutations at putative phosphorylated residues, we revealed that eEF1Bδ1 and eEF1BδL are phosphorylated at S133 and S499, respectively, and these residues are both CDK1 phosphorylation sites. The eEF1BδL S499A mutant more strongly activated HSPA6 promoter-driven reporter than the wild-type protein and S499D mutant. Furthermore, protein phosphatase 1 (PP1) was co-immunoprecipitated with eEF1Bδ1 and eEF1BδL, and PP1 dephosphorylated both proteins in vitro. Thus, this study clarified the role of phosphorylation/dephosphorylation in the functional regulation of eEF1BδL during heat shock.

Transient receptor potential melastatin 7 (TRPM7) is a unique protein functioning as a cation channel as well as a serine/threonine kinase and is highly expressed in immune cells such as lymphocytes and macrophages. TRPM7 kinase‐dead (KD) mouse model has been used to investigate the role of this protein in immune cells; these animals display moderate splenomegaly and ectopic hemopoiesis. The basal TRPM7 current magnitudes in peritoneal macrophages isolated from KD mice were higher; however, the maximum currents, achieved after cytoplasmic Mg2+ washout, were not different. In the present study, we investigated the consequences of TRPM7 kinase inactivation in splenic and peritoneal macrophages. We measured the basal phagocytic activity of splenic macrophages using fluorescent latex beads, pHrodo zymosan bioparticles, and opsonized red blood cells. KD macrophages phagocytized more efficiently and had slightly higher baseline calcium levels compared to WT cells. We found no obvious differences in store‐operated Ca2+ entry between WT and KD macrophages. By contrast, the resting cytosolic pH in KD macrophages was significantly more alkaline than in WT. Pharmacological blockade of sodium hydrogen exchanger 1 (NHE1) reversed the cytosolic alkalinization and reduced phagocytosis in KD macrophages. Basal TRPM7 channel activity in KD macrophages was also reduced after NHE1 blockade. Cytosolic Mg2+ sensitivity of TRPM7 channels measured in peritoneal macrophages was similar in WT and KD mice. The higher basal TRPM7 channel activity in KD macrophages is likely due to alkalinization. Our results identify a novel role for TRPM7 kinase as a suppressor of basal phagocytosis and a regulator of cellular pH.