Groups Fuster & Hediger
Research Focus Group Fuster:
Research Focus Group Fuster: Sodium / proton exchangers (NHEs)
Please visit the external Group Website for more information.
Research Focus Group Hediger:
Our research focuses on membrane proteins that transport substances into and out of cells and cell organelles, and the involvement of these proteins in human diseases.The malfunction or dysregulation of membrane transporters and channels has been linked to major human diseases, including diabetes, hypertension, cardiovascular diseases, cancer, osteoporosis, neurodegenerative diseases and psychiatric disorders. Our long-term goal is to integrate membrane transporter research efforts in physiology/medicine, structural biology and chemistry in order to develop novel therapeutic strategies for the treatment of human diseases.
The study of the physiology and pathology of transporters provides the foundation for a detailed mechanistic investigation of clinically relevant transporters. Determination of the structure and function of mammalian transporter proteins is also important in rational ligand-based drug design, the process of finding new drugs based on knowledge of molecules that bind to the transporter or channel of interest.
Epithelial calcium channels and calcium homeostasis
Calcium is the major inorganic component of the skeleton and an essential messenger in signal transduction in all living cells. The apical calcium entry channel TRPV6 (formerly called CaT1) was identified by expression cloning in our laboratory in 1999 (see article 1) (article 2) (article 3). Together with its kidney homolog, TRPV5 (formerly called ECaC or CaT2) (see article), these channels form a distinct, highly calcium-selective subgroup of the transient receptor potential (TRP) family of cation channels. TRPV6 and TRPV5 play a central role in total body calcium homeostasis (see figure) and their regulation directly affects intestinal calcium absorption, renal calcium excretion and bone metabolism (see article). Thus, understanding the biology and mechanisms of regulation of these channels is of vital importance. We showed that the TRPV6 and TRPV5 channels are regulated by vitamin D and other steroid hormones. We are interested in using these channels as targets for drug development to alter intestinal and renal calcium transport, for example, in patients with kidney stone disease.
Our laboratory elucidated the channel pore properties and tissue distribution of TRPV6 and TRPV5. We also demonstrated that TRPV6 and TRPV5 mRNA expression in vitamin D deficient mice is induced by a single dose of 1,25-dihydroxylvitamin D, with >10-fold increases for TRPV6 and 2-4 fold increases for TRPV5 (see article). The higher responsiveness of intestinal TRPV6 is consistent with the much larger fluctuations of luminal calcium in the intestine compared to kidney.
Biological variability in intestinal calcium absorption and renal reabsorption is a crucial determinant of Ca2+ homeostasis. We hypothesize that polymorphisms in the TRPV6 and TRPV5 genes favor hypercalciuria and renal stone formation, and we have been examining the role of these genes in idiopathic hypercalciuria.
Molecular physiology of iron transport
Iron is vital for most life processes. The cloning and characterization of the mammalian divalent metal ion transporter DMT1 in our laboratory in 1997 was the first demonstration of an active cellular uptake mechanism for Fe2+ (see article). Expression studies of DMT1 revealed that this protein is a H+-coupled cotransporter of several divalent metal ions, including Fe2+, Zn2+, Mn2+, Co2+, Cd2+ and Ni2+. DMT1 is crucial for normal intestinal absorption of iron, as well as in developing red blood cells in which iron is required for hemoglobin synthesis (see article). Iron is also essential for the normal function of many enzymes. Our data show that DMT1 is expressed in the intestinal brush border membrane, and that closely related splice variants are expressed in many other organs including kidney, liver and brain.
DMT1 plays a critical role in the pathogenesis of iron deficiency and overload disorders. A missense mutation, G185R, was identified in DMT1 as the cause of iron deficiency anemia in rodents. Our studies of hereditary hemochromatosis using intestinal biopsy samples revealed that upregulation of DMT1 is tightly associated with the pathogenesis of this common genetic iron overload disease (see article). This upregulation results in excessive iron absorption in the intestine and toxic deposition in major organs such as liver and heart. Dysregulation of DMT1 mRNA expression due to mutations in the HFE gene is likely the cause of abnormal body iron sensing. Our laboratory has shown that intestinal DMT1 mRNA levels are highly regulated and responsive to changes in body iron status, in part via post-transcriptional regulation involving an iron responsive element in the 3'-non-translated region (see article). This regulatory mechanism appears to be disturbed in hemochromatosis.
In addition to DMT1-mediated uptake of inorganic iron in the intestine, there is a second pathway for heme-iron absorption. In fact, heme iron, found in meat, poultry and fish, is two to three times more absorbable than non-heme iron found in plant-based foods. The absorption of heme iron, however, is still poorly understood and my goal is to identify the proteins involved. The aims are to clarify the detailed molecular mechanism of this process, to study how it is regulated to supply appropriate amounts of this essential micronutrient, and to determine what the role of heme iron transport is in patients with iron-deficiency anemia and hemochromatosis.
We are currently using biochemical and electrophysiological approaches to reveal the transport mechanisms of DMT1. Of particular interest are the questions of how exactly DMT1 is coupled to protons, what the molecular basis is for transport-associated ion leaks and what the structural determinants are which define metal ion selectivity.
Amino acid transporters and cancer
Various amino acid transporters have been identified as potential targets for inhibition of cancer progression. For example, the activation of mTOR (mammalian Target Of Rapamycin) is a very important process linking growth signals to nutrient availability and is regulated by the uptake of amino acids such as L-glutamine (the obligate nitrogen donor for nucleotide synthesis). Due to altered glutamine metabolism in cancer, tumor cells can develop a “glutamine addiction” which is required to support macromolecular synthesis for cell proliferation. Glutamine uptake is controlled by a bidirectional transport of L-glutamine mediated by various amino acid transporters. Thus, inhibiting glutamine transport and limiting the delivery of this important nutrient is an important strategy to impede tumor progression (see article).
The goal of our group in collaboration with the chemists groups of Jean-Louis Reymond and Martin Lochner (Department of Chemistry and Biochemistry, University of Bern) is to study the role of amino acid transporters in cancer and to develop specific inhibitors for therapeutic purposes. As of now, some interesting and promising protein targets have been identified based on in silico analyses, literature data mining and in vitro follow-up validation studies. In parallel, structural biology approaches on amino acid transporters are ongoing at our institute (group of Dimitrios Fotiadis), aiming at the determination of high-resolution protein structures suitable for structure-based drug design.
Pathophysiology of zinc transporters
Zinc (Zn2+) is an essential trace element with ubiquitous presence throughout the human body. It plays an important role as a co-factor of many enzymes and is an integral structural component of many proteins, including transcription factors, intracellular signaling enzymes and zinc-finger proteins. In the past years, our group has been focusing on the functional understanding of ZIP1 and ZIP2 zinc transporters with the aim to further understand their mechanisms of transport and how they may be implicated in the pathogenesis of diseases such as cancer and heavy metal toxicity.
We successfully developed a moderate-throughput transport assay to screen for functional modulators of hZIP2 using cadmium as substrate (see article). This has allowed us to further characterize the solute selectivity, pH dependence, and stoichiometry of ZIP2 transport, and also has opened the door to the development of chemical compounds targeting ZIP2 for basic scientific and therapeutic purposes.
Another aspect of our work on zinc transporters refers to the exploitation of data derived from genome-wide association studies (GWAS). They indicated a link between a certain single nucleotide polymorphism (SNP) in the gene encoding ZIP8 and the pathogenesis of hypertension (see article). In collaboration with Daniel Fuster from our institute and Bruno Vogt (Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital Bern), we are setting out to elucidate the pathophysiological role of ZIP8 in the development of hypertension using both in vitro and in vivo approaches.
Uric acid transport
Prenatal exposure of the fetus to pregnancy-related disorders, including preeclampsia (PE), intrauterine growth restriction (IUGR) and gestational diabetes, leads to long-term consequences, such as hypertension, cardiovascular disease or diabetes, later in life. This phenomenon is known as fetal programming. Placental membrane transporters and their regulation affect the intrauterine environment and, therefore, may play a crucial role in the process of fetal programming. Uric acid was shown to play a role in the pathogenesis of PE, a pregnancy-specific disease characterized by hypertension and proteinuria. Hyperuricemia, commonly observed in PE, is associated with adverse perinatal outcome. Therefore, new insights into placental uric acid transport systems and the pathophysiological role of GLUT9 in fetal programming will help to develop prophylactic strategies to prevent the long-term consequences of these pregnancy-specific diseases. In addition, GLUT9 inactivating mutations reduce uricemia, suggesting that this transporter is a potential target for hypouricemic drugs to treat conditions associated with hyperuricemia and uric acid crystal formation such as gout.
Our group is setting out to elucidate the detailed functional mechanisms of this protein using radioisotope- and electrophysiology-based transport assays, structure/function studies, as well as computational and structural biology approaches. In addition, in silico and in vitro small molecule compound screening efforts should lead to the identification of novel GLUT9 inhibitors as lead compounds for future therapeutic applications. These will be facilitated by our collaboration with the group of Prof. Surbek/Dr. Baumann (Department of Obstetrics and Gynecology, Inselspital, Bern), who focus their research activities on the pathophysiological role of GLUT9 in fetal programming.
SLC mini-review series and BioParadigms website
There are currently 52 human transporter gene families belonging to the SLC (solute carrier) series and these families include 395 genes. The SLC tables, originally prepared by the authors of the SLC special issue in the European Journal of Physiology for 42 families, provide the latest updates on these families and their genes, as well as relevant links to gene databases and references. These tables are located on the website of BioParadigms (www.bioparadigms.org), an online scientific resource established by Matthias Hediger in 2004 to facilitate global interaction and information exchange between membrane biologists in academia and industry. Early in 2013, Matthias A. Hediger released as guest editor another series of the currently 52 SLC families in Molecular Aspects of Medicine (Elsevier Ltd.), the special issue being entitled: “The ABC of membrane transporters in health and disease (SLC series)”. Currently, Matthias Hediger serves as Special Advisor on solute carriers to the HUGO Gene Nomenclature Committee (HGNC).
International BioMedical Transporter Conferences are held every two years. The aim is to promote the membrane transporter field, and to review the physiological, pathological and pharmaceutical implications of transporter proteins. The focus is on transporter-based drug discovery strategies, pharmacokinetics, drug delivery, drug elimination and medically relevant transporters as potential novel therapeutic targets. The conference series was originally established in 1999 by Matthias A. Hediger, Peter Meier Abt and Heini Murer, as a joint project between Harvard Medical School and the University of Zurich. Since 2005, the conferences have been organized by Matthias A. Hediger at the University of Bern, together with an international team of scientists (http://www.bioparadigms.org/conference/index.htm).
The next conference will be held in Lausanne at The Olympic Museum, Switzerland from August 6-10, 2017. Click here for more information.