I am a pediatric physician-scientist striving to advance cystic fibrosis clinical care and translational research. Clinically, I am focused on gastrointestinal manifestations of cystic fibrosis, developing diagnostic and therapeutic modalities to improve the gastrointestinal and liver health of those with cystic fibrosis. I also specialize in the clinical management of pediatric pancreatitis and am involved with the international INSPPIRE consortium to study pediatric pancreatitis. In the laboratory, my projects are centered around understanding mechanisms of ion transport in cystic fibrosis tissues and determining how loss of CFTR ion transport leads to pathologic changes in human physiology.

Honors & Awards

  • LeRoy Matthews Physician-Scientist Award, Cystic Fibrosis Foundation

Boards, Advisory Committees, Professional Organizations

  • Member, American Gastroenterological Association
  • Member, American Pancreatic Association
  • Member, Stanford Society of Physician Scholars
  • Member, American Academy of Pediatrics
  • Member, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
  • Member, American Physiological Society

Professional Education

  • Fellowship, Stanford University, Pediatric Gastroenterology, Hepatology, and Nutrition
  • Residency, Stanford University, Pediatrics (2015)
  • MD, University of Illinois, Urbana-Champaign, Medicine (2012)
  • PhD, University of Illinois, Urbana-Champaign, Molecular and Integrative Physiology (2010)
  • BS, University of California, San Diego, Animal Physiology and Neuroscience (2002)

Stanford Advisors

Research & Scholarship


  • CFTR-independent bicarbonate secretion in cystic fibrosis intestines and airways, Stanford University

    Deficient bicarbonate secretion contributes to the hyperviscosity of mucus in CF airways and intestines, and contributes to poor nutrient absorption. We are studying CFTR-independent mechanisms of bicarbonate secretion in CF intestines and airways in order to identify novel therapeutic targets for cystic fibrosis.


    Palo Alto, CA


    • Eric Sibley, Associate Professor, Stanford University
    • Jeffrey Wine, Benjamin Scott Crocker Professor of Human Biology, Stanford University
  • Utilization of MRI to identify early pancreatic and liver disease and develop MRI-based biomarkers of disease for cystic fibrosis, Stanford University

    Pancreatic exocrine dysfunction is a prominent characteristic of cystic fibrosis. Many children with CF become pancreatic insufficient very early in life, while others can remain sufficient for their entire lives. Current serum and imaging modalities to monitor pancreatic function in CF only identify severe dysfunction. The hallmark of CF liver disease is focal biliary cirrhosis, which can lead to portal hypertension. However, serum transaminases are unreliable and liver biopsies are invasive and can miss focal damage. We are developing strategies to use MRI to study pancreatic and liver pathogenesis in CF and develop novel MRI-based biomarkers for CF pancreatic and liver disease.


    Palo Alto, CA


  • Improving Management of Pediatric Pancreatitis


    Lucile Packard Children's Hospital

  • Evaluation of left ventricular myocardial function in cystic fibrosis, Stanford University

    It is well accepted that individuals with cystic fibrosis can develop right ventricular dysfunction secondary to lung disease. However, less is known regarding possible primary cardiac disturbances in CF. Using a CF mouse model we have shown to CFTR is involved in the regulation of cardiomyocyte contraction and loss of CFTR alters intracellular calcium handling and cardiac reserve in response to beta-adrenergic stimulation. We have also utilized strain rate echocardiography to identify subclinical left ventricular dysfunction in cystic fibrosis adults.


    Palo Alto, CA

Lab Affiliations


All Publications

  • Strain rate echocardiography uncovers subclinical left ventricular dysfunction in cystic fibrosis. Journal of cystic fibrosis Sellers, Z. M., McGlocklin, L., Brasch, A. 2015; 14 (5): 654-660


    CFTR is expressed in cardiac myocytes. In mice, lack of CFTR alters cardiomyocyte contraction and Ca(2+) signaling, and decreases cardiac reserve. We undertook a pilot study evaluating left ventricular (LV) function in CF patients using strain and strain rate echocardiography.Echocardiography with tissue Doppler and strain and strain rate imaging were performed in 8 CF adults following pulmonary function tests. Results were compared to literature values obtained in healthy subjects.All CF individuals had normal LV ejection fractions. In contrast, 50% of men and 100% of women with CF had decreased LV systolic strain. Strain rates were significantly decreased in 100% of CF individuals. RV function was normal and LV function did not correlate with lung function.Strain and strain rate echocardiography identified LV systolic abnormalities in CF individuals not detected by conventional echocardiography. We propose that this echocardiography modality may identify subclinical cardiac dysfunction in CF.

    View details for DOI 10.1016/j.jcf.2015.03.010

    View details for PubMedID 25866147

  • Left ventricular and aortic dysfunction in cystic fibrosis mice JOURNAL OF CYSTIC FIBROSIS Sellers, Z. M., Kovacs, A., Weinheimer, C. J., Best, P. M. 2013; 12 (5): 517-524


    Left ventricular (LV) abnormalities have been reported in cystic fibrosis (CF); however, it remains unclear if loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes heart defects independent of lung disease.Using gut-corrected F508del CFTR mutant mice (?F508), which do not develop human lung disease, we examined in vivo heart and aortic function via 2D transthoracic echocardiography and LV catheterization.?F508 mouse hearts showed LV concentric remodeling along with enhanced inotropy (increased +dP/dt, fractional shortening, decreased isovolumetric contraction time) and greater lusitropy (-dP/dt, Tau). Aortas displayed increased stiffness and altered diastolic flow. ?-adrenergic stimulation revealed diminished cardiac reserve (attenuated +dP/dt,-dP/dt, LV pressure).In a mouse model of CF, CFTR mutation leads to LV remodeling with alteration of cardiac and aortic functions in the absence of lung disease. As CF patients live longer, more active lives, their risk for cardiovascular disease should be considered.

    View details for DOI 10.1016/j.jcf.2012.11.012

    View details for Web of Science ID 000324664300015

  • MRP4 and CFTR in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes EUROPEAN JOURNAL OF PHARMACOLOGY Sellers, Z. M., Naren, A. P., Xiang, Y., Best, P. M. 2012; 681 (1-3): 80-87


    Spatiotemporal regulation of cAMP in cardiac myocytes is integral to regulating the diverse functions downstream of ?-adrenergic stimulation. The activities of cAMP phosphodiesterases modulate critical and well-studied cellular processes. Recently, in epithelial and smooth muscle cells, it was found that the multi-drug resistant protein 4 (MRP4) acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl(-) channel, CFTR (cystic fibrosis transmembrane conductance regulator). In the current study we investigated the potential role of MRP4 in regulating intracellular cAMP and ?-adrenergic stimulated contraction rate in cardiac myocytes. Cultured neonatal ventricular myocytes were used for all experiments. In addition to wildtype mice, ?(1)-, ?(2)-, and ?(1)/?(2)-adrenoceptor, and CFTR knockout mice were used. MRP4 expression was probed via Western blot, intracellular cAMP was measured by fluorescence resonance energy transfer, while the functional role of MRP4 was assayed via monitoring of isoproterenol-stimulated contraction rate. We found that MRP4 is expressed in mouse neonatal ventricular myocytes. A pharmacological inhibitor of MRP4, MK571, potentiated submaximal isoproterenol-stimulated cAMP accumulation and cardiomyocyte contraction rate via ?(1)-adrenoceptors. CFTR expression was critical for submaximal isoproterenol-stimulated contraction rate. Interestingly, MRP4-dependent changes in contraction rate were CFTR-dependent, however, PDE4-dependent potentiation of contraction rate was CFTR-independent. We have shown, for the first time, a role for MRP4 in the regulation of cAMP in cardiac myocytes and involvement of CFTR in ?-adrenergic stimulated contraction. Together with phosphodiesterases, MRP4 must be considered when examining cAMP regulation in cardiac myocytes.

    View details for DOI 10.1016/j.ejphar.2012.02.018

    View details for Web of Science ID 000301799400012

    View details for PubMedID 22381067

  • Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+-activated Cl- channel activity to maintain contraction rate JOURNAL OF PHYSIOLOGY-LONDON Sellers, Z. M., De Arcangelis, V., Xiang, Y., Best, P. M. 2010; 588 (13): 2417-2429


    The physiological role of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiomyocytes remains unclear. Using spontaneously beating neonatal ventricular cardiomyocytes from wild-type (WT) or CFTR knockout (KO) mice, we examined the role of CFTR in the modulation of cardiomyocyte contraction rate. Contraction rates of spontaneously beating myocytes were captured by video imaging. Real-time changes in intracellular ([Ca(2+)](i)) and protein kinase A (PKA) activity were measured by fura-2 and fluorescence resonance energy transfer, respectively. Acute inhibition of CFTR in WT cardiomyocytes using the CFTR inhibitor CFTR(inh)-172 transiently inhibited the contraction rate. By contrast, cardiomyocytes from CFTR KO mice displayed normal contraction rates. Further investigation revealed that acute inhibition of CFTR activity in WT cardiomyocytes activated L-type Ca(2+) channels, leading to a transient increase of [Ca(2+)](i) and inhibition of PKA activity. Additionally, we found that contraction rate normalization following acute CFTR inhibition in WT cardiomyocytes or chronic deletion in cardiomyocytes from CFTR KO mice requires the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) and Ca(2+)-activated Cl(-) channels (CaCC) because simultaneous addition of myristoylated-autocamtide-2-related inhibitory peptide or niflumic acid and CFTR(inh)-172 to WT cardiomyocytes or treatment of cardiomyoctes from CFTR KO mice with these agents caused sustained attenuation of contraction rates. Our results demonstrate that regulation of cardiomyocyte contraction involves CFTR. They also reveal that activation of CaMKII and CaCC compensates for loss of CFTR function. Increased dependence on CaMKII upon loss of CFTR function might leave cystic fibrosis patients at increased risk of heart dysfunction and disease.

    View details for DOI 10.1113/jphysiol.2010.188334

    View details for Web of Science ID 000279406600015

    View details for PubMedID 20442264

  • A critical GxxxA motif in the gamma(6) calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current JOURNAL OF PHYSIOLOGY-LONDON Lin, Z., Witschas, K., Garcia, T., Chen, R., Hansen, J. P., Sellers, Z. M., Kuzmenkina, E., Herzig, S., Best, P. M. 2008; 586 (22): 5349-5366


    The eight members of the calcium channel gamma subunit family are integral membrane proteins that regulate the expression and behaviour of voltage and ligand gated ion channels. While a subgroup consisting of gamma(2), gamma(3), gamma(4) and gamma(8) (the TARPs) modulate AMPA receptor localization and function, the gamma(1) and gamma(6) subunits conform to the original description of these proteins as regulators of voltage gated calcium channels. We have previously shown that the gamma(6) subunit is highly expressed in atrial myocytes and that it is capable of acting as a negative modulator of low voltage activated calcium current. In this study we extend our understanding of gamma(6) subunit modulation of low voltage activated calcium current. Using engineered chimeric constructs, we demonstrate that the first transmembrane domain (TM1) of gamma(6) is necessary for its inhibitory effect on Cav3.1 current. Mutational analysis is then used to identify a unique GxxxA motif within TM1 that is required for the function of the subunit strongly suggesting the involvement of helix-helix interactions in its effects. Results from co-immunoprecipitation experiments confirm a physical association of gamma(6) with the Cav3.1 channel in both HEK cells and atrial myocytes. Single channel analysis reveals that binding of gamma(6) reduces channel availability for activation. Taken together, the results of this study provide both a molecular and a mechanistic framework for understanding the unique ability of the gamma(6) calcium channel subunit to modulate low voltage activated (Cav3.1) calcium current density.

    View details for DOI 10.1113/jphysiol.2008.159111

    View details for Web of Science ID 000261274600012

    View details for PubMedID 18818244

  • Heat-stable enterotoxin of Escherichia coli (STa) can stimulate duodenal HCO3- secretion via a novel GC-C- and CFTR-independent pathway FASEB JOURNAL Sellers, Z. M., Mann, E., Smith, A., Ko, K. H., Giannella, R., Cohen, M. B., Barrett, K. E., Dong, H. 2008; 22 (5): 1306-1316


    The heat-stable enterotoxin of Escherichia coli (STa) is a potent stimulant of intestinal chloride and bicarbonate secretion. Guanylyl cyclase C (GC-C) has been shown to be the primary receptor involved in mediating this response. However, numerous studies have suggested the existence of an alternative STa-binding receptor. The aims of this study were to determine whether a non-GC-C receptor exists for STa and what is the functional relevance of this for intestinal bicarbonate secretion in mice. (125)I-STa-binding experiments were performed with intestinal mucosae from GC-C knockout (KO) and wild type (WT) mice. Subsequently, the functional relevance of an alternative STa-binding receptor was explored by examining STa-, uroguanylin-, and guanylin-stimulated duodenal bicarbonate secretion (DBS) in GC-C KO mice in vitro and in vivo. Significant (125)I-STa-binding occurred in the proximal small intestines of GC-C KO and WT mice. Analysis of binding coefficients and pH dependence showed that (125)I-STa-binding in GC-C KO mice involved a receptor distinct from that of WT mice. Functionally, STa, uroguanylin, and guanylin all stimulated a significant increase in DBS in GC-C KO mice. Uroguanylin- and guanylin-stimulated DBS were significantly inhibited by glibenclamide, but not by 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS). However, STa-stimulated DBS was unaffected by glibenclamide but inhibited by DIDS. Taken together, our results suggest that alternative, non-GC-C, receptors likely exist for STa, uroguanylin, and guanylin in the intestines of mice. While uroguanylin- and guanylin-stimulated DBS are cystic fibrosis transmembrane conductance regulator (CFTR) dependent, STa-stimulated DBS is CFTR independent. Further understanding of this alternative receptor and its signaling pathway may provide important insights into rectification of intestinal bicarbonate secretion in cystic fibrosis.

    View details for DOI 10.1096/fj.06-7540com

    View details for Web of Science ID 000255898700004

    View details for PubMedID 18096816

  • Calcium channel gamma subunits: a functionally diverse protein family CELL BIOCHEMISTRY AND BIOPHYSICS Chen, R., Deng, T., Garcia, T., Sellers, Z. M., Best, P. M. 2007; 47 (2): 178-186


    The calcium channel gamma subunits comprise an eight-member protein family that share a common topology consisting of four transmembrane domains and intracellular N- and C-termini. Although the first gamma subunit was identified as an auxiliary subunit of a voltage-dependent calcium channel, a review of phylogenetic, bioinformatic, and functional studies indicates that they are a functionally diverse protein family. A cluster containing gamma1 and gamma6 conforms to the original description of the protein family as they seem to act primarily as subunits of calcium channels expressed in muscle. Members of a second cluster (gamma2, gamma3, gamma4, gamma8) function as regulators of AMPA receptor localization and function in the brain and are collectively known as TARPs. The function of members of the third cluster (gamma5, gamma7) remains unclear. Our analysis shows that the members of each cluster contain conserved regulatory motifs that help to differentiate the groups. However, the physiological significance of these motifs in many cases remains to be demonstrated.

    View details for DOI 10.1007/s12013-007-0002-0

    View details for Web of Science ID 000247447800002

    View details for PubMedID 17652770

  • Esomeprazole therapy for gastric acid hypersecretion in children with cystinosis PEDIATRIC NEPHROLOGY Dohil, R., Fidler, M., Barshop, B., Newbury, R., Sellers, Z., Deutsch, R., Schneider, J. 2005; 20 (12): 1786-1793


    Oral cysteamine therapy prevents natural disease progression in children with cystinosis, but it may cause severe gastrointestinal (GI) symptoms through gastric acid-hypersecretion. The purpose of this study was to assess the value of esomeprazole in controlling cysteamine-induced acid-hypersecretion and GI symptoms in children with cystinosis. Subjects underwent upper GI endoscopy and biopsy, serum gastrin and cysteamine measurements as well as acid secretion studies (basal, maximal and peak acid output, BAO, MAO, PAO) before and during esomeprazole therapy. A symptom score (maximum 14 points) was devised to monitor symptoms. Twelve children (mean age 5.8 years) were studied. Cysteamine ingestion resulted in mean MAO and PAO significantly higher than mean BAO, both before and during esomeprazole therapy. PAO was usually within 60 min of cysteamine ingestion. Esomeprazole therapy significantly reduced MAO (P<0.01) and PAO (P<0.01). The mean symptom score fell from 6.4 to 0.7 (P<0.0001) during esomeprazole therapy. The mean final dose of esomeprazole was 1.7 mg/kg per day (range 0.7 mg/kg per day to 2.75 mg/kg per day). Plasma cysteamine levels were not affected by acid-suppression therapy. One child had multi-nucleated parietal cells. Cysteamine-induced gastric acid-hypersecretion and GI symptoms are dramatically reduced with esomeprazole therapy. Esomeprazole does not alter cysteamine absorption and is very well tolerated in children.

    View details for DOI 10.1007/s00467-005-2027-1

    View details for Web of Science ID 000233349900017

    View details for PubMedID 16133039

  • Heat-stable enterotoxin of Escherichia coli stimulates a non-CFTR-mediated duodenal bicarbonate secretory pathway AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Sellers, Z. M., Childs, D., Chow, J. Y., SMITH, A. J., Hogan, D. L., Isenberg, J. I., Dong, H., Barrett, K. E., Pratha, V. S. 2005; 288 (4): G654-G663


    The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is an important pathway for duodenal mucosal bicarbonate secretion. Duodenal biopsies from CF patients secrete bicarbonate in response to heat-stable enterotoxin from Escherichia coli (STa) but not cAMP. To explore the mechanism of STa-induced bicarbonate secretion in CF more fully, we examined the role of CFTR in STa-stimulated duodenal bicarbonate secretion in mice. In vivo, the duodenum of CFTR (-/-) or control mice was perfused with forskolin (10(-4) M), STa (10(-7) M), uroguanylin (10(-7) M), 8-bromoguanosine 3',5'-cGMP (8-Br-cGMP) (10(-3) M), genistein (10(-6) M) plus STa, or herbimycin A (10(-6) M) plus STa. In vitro, duodenal mucosae were voltage-clamped in Ussing chambers, and bicarbonate secretion was measured by pH-stat. The effect of genistein, DIDS (10(-4) M), and chloride removal was also studied in vitro. Control, but not CF, mice produced a significant increase in duodenal bicarbonate secretion after perfusion with forskolin, uroguanylin, or 8-Br-cGMP. However, both control and CF animals responded to STa with significant increases in bicarbonate output. Genistein and herbimycin A abolished this response in CF mice but not in controls. In vitro, STa-stimulated bicarbonate secretion in CF tissues was inhibited by genistein, DIDS, and chloride-free conditions, whereas bicarbonate secretion persisted in control mice. In the CF duodenum, STa can stimulate bicarbonate secretion via tyrosine kinase activity resulting in apical Cl(-)/HCO(3)(-) exchange. Further studies elucidating the intracellular mechanisms responsible for such non-CFTR mediated bicarbonate secretion may lead to important therapies for CF.

    View details for DOI 10.1152/ajpgi.00386.2004

    View details for Web of Science ID 000227564400009

    View details for PubMedID 15513951

  • Na+/Ca2+ exchange regulates Ca2+-dependent duodenal mucosal ion transport and HCO3- secretion in mice AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Dong, H., Sellers, Z. M., Smith, A., Chow, J. Y., Barrett, K. E. 2005; 288 (3): G457-G465


    Stimulation of muscarinic receptors in duodenal mucosa raises intracellular Ca(2+), which regulates ion transport, including HCO(3)(-) secretion. However, the underlying Ca(2+) handling mechanisms are poorly understood. The aim of the present study was to determine whether Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of duodenal mucosal ion transport and HCO(3)(-) secretion by controlling Ca(2+) homeostasis. Mouse duodenal mucosa was mounted in Ussing chambers. Net ion transport was assessed as short-circuit current (I(sc)), and HCO(3)(-) secretion was determined by pH-stat. Expression of NCX in duodenal mucosae was analyzed by Western blot, and cytosolic Ca(2+) in duodenocytes was measured by fura 2. Carbachol (100 muM) increased I(sc) in a biphasic manner: an initial transient peak within 2 min and a later sustained plateau starting at 10 min. Carbachol-induced HCO(3)(-) secretion peaked at 10 min. 2-Aminoethoxydiphenylborate (2-APB, 100 muM) or LiCl (30 mM) significantly reduced the initial peak in I(sc) by 51 or 47%, respectively, and abolished the plateau phase of I(sc) without affecting HCO(3)(-) secretion induced by carbachol. Ryanodine (100 muM), caffeine (10 mM), and nifedipine (10 muM) had no effect on either response to carbachol. In contrast, nickel (5 mM) and KB-R7943 (10-30 muM) significantly inhibited carbachol-induced increases in duodenal mucosal I(sc) and HCO(3)(-) secretion. Western blot analysis showed expression of NCX1 proteins in duodenal mucosae, and functional NCX in duodenocytes was demonstrated in Ca(2+) imaging experiments where Na(+) depletion elicited Ca(2+) entry via the reversed mode of NCX. These results indicate that NCX contributes to the regulation of Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion that results from stimulation of muscarinic receptors.

    View details for DOI 10.1152/ajpgi.00381.2004

    View details for Web of Science ID 000226833100007

    View details for PubMedID 15499079

  • A role for CagA/VacA in Helicobacter pylori inhibition of murine duodenal mucosal bicarbonate secretion DIGESTIVE DISEASES AND SCIENCES Tuo, B. G., Sellers, Z. M., SMITH, A. J., Barrett, K. E., Isenberg, J. I., Dong, H. 2004; 49 (11-12): 1845-1852


    Duodenal mucosal bicarbonate secretion is diminished in patients with Helicobacter pylori (HP)-associated duodenal ulcer disease. We examined whether HP water extracts inhibit murine duodenal mucosal bicarbonate secretion in vitro, and the mechanisms involved. Murine duodenal mucosae were mounted in Ussing chambers. Short-circuit current and bicarbonate secretion was measured. CagA/VacA-positive HP water extract (HPWE+/+) markedly inhibited PGE2-, carbachol-, or the calcium ionophore A23187-stimulated bicarbonate secretion in a dose-dependent manner. While 3-isobutyl-1-methylxanthine-stimulated bicarbonate secretion was not affected by HPWE+/+, HPWE+/+ did diminish forskolin-stimulated bicarbonate secretion. HPWE+/+ markedly diminished PGE2-induced increases in duodenal mucosal cAMP. CagA/VacA of HP decreases Ca2+-mediated bicarbonate secretion downstream of increases in intracellular Ca2+. Dimunition of PGE2-stimulated bicarbonate secretion occurs, in part, by inhibition of adenylate cyclase, which leads to decreased cAMP levels. The ability of virulent HP strains to inhibit duodenal bicarbonate secretion through multiple intracellular pathways likely contributes to the pathogenesis of HP-associated duodenal ulcer disease.

    View details for Web of Science ID 000225971000022

    View details for PubMedID 15628715

  • 5-HT induces duodenal mucosal bicarbonate secretion via cAMP- and Ca2+-dependent signaling pathways and 5-HT4 receptors in mice AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Tuo, B. G., Sellers, Z., Paulus, P., Barrett, K. E., Isenberg, J. I. 2004; 286 (3): G444-G451


    In previous studies, we have found that 5-hydroxytryptamine (5-HT) is a potent stimulant of duodenal mucosal bicarbonate secretion (DMBS) in mice. The aim of the present study was to determine the intracellular signaling pathways and 5-HT receptor subtypes involved in 5-HT-induced DMBS. Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. 5-HT receptor involvement in DMBS was inferred from pharmacological studies by using selective 5-HT receptor antagonists and agonists. The expression of 5-HT(4) receptor mRNA in duodenal mucosa and epithelial cells was analyzed by RT-PCR. cAMP-dependent signaling pathway inhibitors MDL-12330A, Rp-cAMP, and H-89 and Ca(2+)-dependent signaling pathway inhibitors verapamil and W-13 markedly reduced 5-HT-stimulated duodenal bicarbonate secretion and short-circuit current (I(sc)), whereas cGMP-dependent signaling pathway inhibitors NS-2028 and KT-5823 failed to alter these responses. Both SB-204070 and high-dose ICS-205930 (selective 5-HT(4) receptor antagonists) markedly inhibited 5-HT-stimulated bicarbonate secretion and I(sc), whereas methiothepine (5-HT(1) receptor antagonist), ketanserin (5-HT(2) receptor antagonist), and a low concentration of ICS-205930 (5-HT(3) receptor antagonist) had no effect. RS-67506 (partial 5-HT(4) receptor agonist) concentration-dependently increased bicarbonate secretion and I(sc), whereas 5-carboxamidotryptamine (5-HT(1) receptor agonist), alpha-methyl-5-HT (5-HT(2) receptor agonist), and phenylbiguanide (5-HT(3) receptor agonist) did not significantly increase bicarbonate secretion or I(sc). RT-PCR analysis confirmed the expression of 5-HT(4) receptor mRNA in murine duodenal mucosa and epithelial cells. These results demonstrate that 5-HT regulates DMBS via both cAMP- and Ca(2+)-dependent signaling pathways and 5-HT(4) receptors located in the duodenal mucosa and/or epithelial cells.

    View details for DOI 10.1152/ajpgi.00105.2003

    View details for Web of Science ID 000188783400011

    View details for PubMedID 14576083

  • A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Rao, S. P., Sellers, Z., Crombie, D. L., Hogan, D. L., Mann, E. A., Childs, D., Keely, S., Sheil-Puopolo, M., Giannella, R. A., Barrett, K. E., Isenberg, J. I., Pratha, V. S. 2004; 286 (1): G95-G101


    Luminal acidification provides the strongest physiological stimulus for duodenal HCO3- secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated HCO3- secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal HCO3- secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated HCO3- secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal HCO3- secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal HCO3- secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.

    View details for DOI 10.1152/ajpgi.00087.2003

    View details for Web of Science ID 000187118600013

    View details for PubMedID 12881226

  • The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine JOURNAL OF PEDIATRICS Dohil, R., Newbury, R. O., Sellers, Z. M., Deutsch, R., Schneider, J. A. 2003; 143 (2): 224-230


    Cysteamine prevents organ damage in children with cystinosis, but may cause gastrointestinal (GI) symptoms. In this study we evaluated the nature of GI disease, and the value of omeprazole in controlling GI symptoms in these children.Upper GI disease was evaluated with endoscopy, gastrin levels, and acid secretion studies after oral administration of cysteamine, before and after 16 weeks of therapy with omeprazole. A symptom score was devised.Eleven children (mean age, 5.7 years) were studied. After cysteamine ingestion, before and after omeprazole therapy, the mean maximum acid output was significantly higher than the mean basal acid output. The maximum acid output was measured within 60 minutes of cysteamine ingestion and was reduced by omeprazole therapy (P<.01). The mean peak gastrin level was 30 minutes postcysteamine and was higher than baseline (P<.01). The initial mean symptom score (maximum score, 14) was 6.9 and fell to 0.7 (P<.0001) after 16 weeks of omeprazole therapy. At endoscopy, two children had diffuse gastric nodularity, and nearly all had cystine crystal deposits.GI symptoms in children with cystinosis receiving cysteamine are often acid-mediated and improve with omeprazole. Cystine crystals were detected in the GI tract and may signify inadequate treatment with cysteamine.

    View details for DOI 10.1067/S0022-3476(03)00281-6

    View details for Web of Science ID 000185118300018

    View details for PubMedID 12970638

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