F. Javier Alvarez-Leefmans, MD, PhD

Department:
Pharmacology/Toxicology
Email:
francisco.alvarez-leefmans@wright.edu

Research Interests

                 Research in my laboratory focuses on the molecular and cellular physiology of carrier protein molecules that actively transport chloride ions (Cl-) across the plasma membrane of neurons and epithelial cells. Specifically, we study some members of the cation-coupled-chloride contransporter gene/protein family SLC12A: the Na+, K+, 2 Cl- cotransporters (NKCC1 and NKCC2) and the K+-Cl- cotransporters (KCC1, 2, 3 and 4). These carrier proteins play key roles in: intracellular Cl- homeostasis in neurons, GABA- and glycine-mediated synaptic signaling, neuronal development, sensory transduction including nociception, transepithelial salt transport, cell water volume control, and extracellular K+ muffling. Not surprisingly, altered function of these proteins underlies several pathologies and hence they have become significant targets for therapeutic interventions and translational research. To study the function of these proteins we use state-of-the-art live-cell imaging microscopy and fluorescent probes for measuring and manipulating intracellular ions and water in dissociated neurons and epithelial cells. Some of these optical methods have been developed in our lab, and are used in conjunction with molecular methods, knockout models, and several microanatomical techniques. Our current research involves two projects:

  1. Mechanisms regulating intracellular chloride in primary afferent neurons and their impact on GABA-mediated presynaptic inhibition and sensory transduction. This project aims at understanding the molecular mechanisms that determine intracellular Cl- concentration in primary afferent neurons, their regulation, and the role they play in presynaptic inhibition, acute somatic pain, neurogenic inflammation and proprioception.
  1. Roles of cation-coupled-chloride contransporters of choroid plexus epithelial cells in the regulation of cerebrospinal fluid ion composition. The choroid plexus epithelial cells (CPECs) form the blood-cerebrospinal fluid (CSF) barrier. CPECs secrete CSF and regulate its electrolyte composition. Regulation of CSF ion levels is fundamental for maintaining normal brain function. The overarching goal of this project is to understand how NKCC1, KCCs and aquaporins control the ion composition of the cerebrospinal fluid. Current emphasis is on the molecular and cellular mechanisms used by CPECs to regulate and maintain the CSF K+ concentration, a fundamental problem of broad physiological significance. CSF composition has a major impact on the fluid microenvironment of neurons and glial cells, and vice versa. Extracellular K+ homeostasis is critical for normal brain function; small changes in extracellular K+ profoundly affect neuronal excitability and osmotic water balance of glial cells and neurons.

Selected publications

Peer reviewed articles

  1. Alvarez-Leefmans F.J. Differences are more than just methodological. Journal of Physiology, 2021 [physoc.onlinelibrary.wiley]
  2. Alvarez-Leefmans FJ. Apical NKCC1 of choroid plexus epithelial cells works in the net inward flux mode under basal conditions, maintaining intracellular Cl− and cell volume. Journal of Physiology. 598 (21): 4733-4736, 2020. doi: 10.1113/JP279867. PMID: 32870510 [Pubmed]
  3. Alvarez-Leefmans F.J. Rebuttal to N. MacAulay and C.R. Rose. CrossTalk opposing view: NKCC1 in the luminal membrane of choroid plexus is outwardly directed under basal conditions and contributes directly to cerebrospinal fluid secretion. Journal of Physiology 598(21):4741-4742, 2020. doi: 10.1113/JP280493. PMID: 32870502 [Pubmed]
  4. Gregoriades JMC, Madaris A, Alvarez FJ, Alvarez-Leefmans FJ. Genetic and pharmacological inactivation of apical Na+, K+, 2Cl- cotransporter 1 in choroid plexus epithelial cells reveals the physiological function of the cotransporter. American Journal of Physiology-Cell Physiology 316: C525-C544, 2019. [Pubmed]
  5. Blanco VM, Márquez MS, Alvarez-Leefmans FJ. Parallel changes in intracellular water volume and pH induced by NH3 /NH4+ exposure in single neuroblastoma cells. Cell Physiol Biochem. 32(7): 57-76, 2013. [Pubmed]
  6. Alvarez-Leefmans FJ. Intracellular Chloride Regulation. In: Cell Physiology Sourcebook (4th ed.), edited by Sperelakis N. London: Academic Press-Elsevier, p. 221-259. (2012). [Google Books]
  7. Mao S, Garzon-Muvdi T, Di Fulvio M, Chen Y, Delpire E, Alvarez FJ, Alvarez-Leefmans, FJ. Molecular and functional expression of cation-chloride cotransporters in dorsal root ganglion neurons during postnatal maturation. Journal of Neurophysiology 108(3): 834-852, 2012. [Pubmed]
  8. Hamann S, Herrera-Perez JJ, Zeuthen T, Alvarez-Leefmans FJ. Cotransport of water by the Na+-K+-2Cl- cotransporter NKCC1 in mammalian epithelial cells. Journal of Physiology 588:4089-4101, 2010. [Pubmed]
  9. Ares GR, Caceres PS, Alvarez-Leefmans FJ, Ortiz PA. cGMP decreases surface NKCC2 levels in the thick ascending limb: Role of phosphodiesterase 2 (PDE2). American Journal of Physiology. 295(4): F877-F887 (2008). [Pubmed]
  10. Rocha-González HI, Mao S, Alvarez-Leefmans FJ. Na+,K+,2Cl- Cotransport and Intracellular Chloride Regulation in Rat Primary Sensory Neurons: Thermodynamic and Kinetic Aspects. Journal of Neurophysiology 100(1):169-184 (2008). [Pubmed]
  11. Muñoz A, Méndez P, DeFelipe J, Alvarez-Leefmans FJ. Cation-chloride cotransporters and GABA-ergic innervation in the human epileptic hippocampus. Epilepsia. 48(4):663-673 (2007). [Pubmed,]
  12. Alvarez-Leefmans FJ, Herrera-Perez JJ, Marquez MS, Blanco VM. Simultaneous measurement of water volume and pH in single cells using BCECF and fluorescence imaging microscopy. Biophysical Journal 90:608-618 (2006). [Pubmed]
  13. Granados-Soto V, Arguelles CF, Alvarez-Leefmans FJ. Peripheral and central antinociceptive action of Na+-K+-2Cl– cotransporter blockers on formalin-induced nociception in rats. Pain 114: 231-238, 2005. [Pubmed]
  14. Hamann S, Herrera-Pérez JJ, Bundgaard M, Alvarez-Leefmans FJ, Zeuthen T. Water permeability of Na+-K+-2Cl- cotransporters in mammalian epithelial cells. Journal of Physiology (London) 568.1:123-135, 2005. [Pubmed]
  15. Marty S, Wehrlé R, Alvarez-Leefmans FJ, Gasnier B, Sotelo C. Postnatal maturation of Na+,K+,2Cl- co-transporter immunoreactivity and inhibitory synaptogenesis in the rat hippocampus. European Journal of Neuroscience 15:1-15, 2002. [Pubmed]
  16. Alvarez-Leefmans FJ, León-Olea M, Mendoza-Sotelo, J, Alvarez FJ, Antón B, Garduño R. Immuno- localization of the Na+-K+-2Cl- cotransporter in peripheral nervous tissues of vertebrates. Neuroscience 104: 569-582, 2001. (PMID: 11377856) [Pubmed]
  17. Alvarez-Leefmans FJ, Altamirano J, Crowe WE. Use of ion-selective microelectrodes and fluorescent probes to measure cell volume. In: Kraicer J, Dixon SJ, eds. Measurement and manipulation of intracellular ions. San Diego: Academic Press, 1995, p. 361-391. [Abstract]
  18. Crowe WE, Altamirano J, Huerto L, Alvarez-Leefmans FJ. Cell volume changes in single N1E-115 neuroblastoma cells measured with a fluorescent probe. Neuroscience 69: 283-296, 1995. [Pubmed]
  19. Alvarez-Leefmans FJ, Gamino SM, Giraldez F, Nogueron I. Intracellular chloride regulation in amphibian dorsal root ganglion neurones studied with ion-selective microelectrodes. Journal of Physiology 406:225-246,1988. [Pubmed]

Books

  1.    Alvarez-Leefmans, F.J. and Russell, J.M.  Chloride Channels and Carriers in Nerve, Muscle, and Glial Cells. Plenum Press, New York, 1990. ISBN 0-306-43426-1 [Springer] [Amazon]
  2.    Alvarez-Leefmans, F.J. Las neuronas de Don Santiago: Santiago Ramón y Cajal. Consejo Nacional Para la Cultura y las Artes, Pangea Editores. México,1994. ISBN 968-617-758-2      [Amazon]
  3.    De la Fuente, R. and Alvarez-Leefmans, F.J.  Biología de la Mente (Biology of Mind). Fondo de Cultura Económica and El Colegio Nacional. México. 1998. (Sixth printing, 2017).                ISBN 978-968-16-5124-4. 532 pp. ISBN 978-607-16-3089-6. [Amazon]
  4.   Alvarez-Leefmans, F.J. and Delpire, E. Physiology and Pathology of Chloride Transporters and Channels in the Nervous System. From molecules to diseases. Elsevier- Academic Press, San    Diego, CA. 2009. ISBN 978-0-12-374373-2 [Amazon]

Articles about Dr. Alvarez-Leefmans’ work

Naftalin, R. Water cotransport in pigmented epithelial cells. Journal of physiology 588:4063-4064, 2010 [Pubmed]

Vidal Pérez-Treviño, GS. NKCC1 cotransporters: keeping an 'ion' them. Journal of Physiology 589.4:781–782, 2011. [Pubmed]

Friauf, E. Physiology and Pathology of Chloride Transporters and Channels in the Nervous System: From Molecules to Diseases. The Physiologist 53 (6): 239, 2010. [Full text]

Kahle, KT and Staley, K. Altered neuronal chloride homeostasis and excitatory GABAergic signaling in human temporal lobe epilepsy. Epilepsy Currents, (American Epilepsy Society) 8 (2) 51–53, 2008. [Pubmed]

Various authors: Comments on CrossTalk 48, Journal of Physiology, 2021: Apical NKCC1 of choroid plexus epithelial cells works in the net inward flux mode under basal conditions, maintaining intracellular Cl− and cell volume/NKCC1 in the luminal membrane of choroid plexus is outwardly directed under basal conditions and  contributes directly to cerebrospinal fluid secretion [physoc.onlinelibrary.wiley]

Trainees during the last five years
Master's & Ph.D. Students

  • Héctor Rocha-González (currently at Department of Pharmacobiology, CINVESTAV, Mexico).
  • Tomás Garzon-Muvdi, (currently at Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Md.)
  • Gisela Llobet (currently at Universidade Federal do Rio Grande do Sul–UFRGS-, Brazil).
  • Jeannine M. Crum (current Ph.D. student at Wright State University)
  • Pankaj Patyal (University of Arkansas)

Postdocs

  • Mauricio Di Fulvio (currently independent researcher at Wright State University)
  • Shihong Mao (currently at Wayne State University School of Medicine, Detroit)
  • Karin Flues (currently at Wright State University)
  • Victor Blanco (currently at University of Cincinnati)

Selected honors
1998-2000: President, Latin American Biophysical Society (SOBLA).
1997-1998: Fellow of the John Simon Guggenheim Memorial Foundation, New York.
2000: Merit Award, Spanish Biophysical Society, Alicante, Spain, 2000.
2005: Elected Member. Academy of Sciences of Latin America (ACAL).
2008: Fellow of the National Academy of Medicine, México.

Education History

M.D.: National University of Mexico

Ph.D.: University College London, Neurophysiology, University of London, UK

Postdoctoral: University College London, Biophysics, University of London, UK

Postdoctoral: Cambridge University, Physiological Laboratory, UK

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