Kazuharu Furutani

Bio: Kazuharu Furutani is an academic researcher from University of California, Davis. The author has contributed to research in topics: hERG & Gastrin. The author has an hindex of 13, co-authored 32 publications receiving 1754 citations. Previous affiliations of Kazuharu Furutani include Tokushima Bunri University & Kyoto Pharmaceutical University.

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

Abstract: Inwardly rectifying K+ (Kir) channels allow K+ to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are ...

Basolateral Mg2+ Extrusion via CNNM4 Mediates Transcellular Mg2+ Transport across Epithelia: A Mouse Model

Abstract: Transcellular Mg(2+) transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg(2+) extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg(2+) extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg(2+) by exchanging intracellular Mg(2+) with extracellular Na(+). Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg(2+) extrusion activity. These results demonstrate the crucial importance of Mg(2+) extrusion by CNNM4 in organismal and topical regulation of magnesium.

Mutational and In Silico Analyses for Antidepressant Block of Astroglial Inward-Rectifier Kir4.1 Channel

Abstract: Drug interaction with target proteins including ion channels is essential for pharmacological control of various cellular functions, but the majority of its molecular mechanisms is still elusive. We recently found that a series of antidepressants preferentially block astroglial K(+)-buffering inwardly rectifying potassium channel (Kir) 4.1 channels over Kir1.1 channels. Here, using electrophysiological analyses of drug action on mutated Kir4.1 channel as well as computational analyses of three-dimensional (3D) arrangements of the ligands (i.e., bidirectional analyses), we examined the underlying mechanism for the antidepressant-Kir4.1 channel interaction. First, the effects of the selective serotonin reuptake inhibitor fluoxetine and the tricyclic antidepressant nortriptyline on chimeric and site-directed mutants of Kir4.1 expressed in Xenopus laevis oocytes were examined using the two-electrode voltage-clamp technique. Two amino acids, Thr128 and Glu158, on transmembrane domain 2 were critical for the drug inhibition of the current. The closed and open conformation models of the Kir4.1 pore suggested that both residues faced the central cavity, and they were positioned within a geometrical range capable of interacting with the drugs. Second, to represent molecular properties of active ligands in geometric terms, a 3D quantitative structure-activity relationship model of antidepressants was generated, which suggested that they share common features bearing a hydrogen bond acceptor and a positively charged moiety. 3D structures and physicochemical features of receptor and ligand were fitted together. Our results strongly suggest that antidepressants interact with Kir4.1 channel pore residues by hydrogen bond and ionic interactions, which account for their preferential inhibitory action on Kir4.1 current. This study may represent a possible general approach for the understanding of the mechanism of ligand-protein interactions.

Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity

Abstract: Functional crosstalk between cell-surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)-mediated Ca2+-induced Ca2+ release and the subsequent opening of small-conductance Ca2+-activated K+ (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP-DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long-term depression (LTD) at parallel fiber–PC synapses adversely established long-term potentiation in the JP-DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP-DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca2+-mediated communication between voltage-gated Ca2+ channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles

Abstract: Inwardly rectifying K+ (Kir) channels allow K+ to move more easily into rather than out of the cell. They have diverse physiological functions depending on their type and their location. There are ...

Magnesium in Man: Implications for Health and Disease

Abstract: Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

Physiology of astroglia

Abstract: Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Abstract: Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4α, as mediators of the sex-dependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.