Francisco J. Alvarez-Leefmans, M.D., Ph.D.

Professor

Campus address: 063 Medical Sciences
Phone: (937) 775-3355
Fax: (937) 775-7221
francisco.alvarez-leefmans@wright.edu

Education

M.D. (1973) National University of Mexico
Ph.D. (1976) University College London, Neurophysiology, University of London, UK
Postdoctoral (1976-1979) University College London, Biophysics, University of London, UK
Postdoctoral (1979-1980), Cambridge University, Physiological Laboratory, UK

Research Interests

Neuroscience: Cellular and molecular physiology of ion transport, cell volume, and pain

Research in my laboratory involves two tightly linked areas:

1. Mechanisms regulating intracellular chloride in neurons and their impact on GABA-mediated synaptic inhibition. The long-term objective is to understand the molecular mechanisms that determine the concentration of intracellular chloride (Cl-) in primary afferent neurons (PANs), their regulation and the role they play in acute somatic pain and neurogenic inflammation. PANs convey sensory information from the body to the central nervous system. Electric signals arising from peripheral sensory receptors enter the spinal cord and the brain stem through the central processes of PANs and ultimately evoke sensations such as touch, warmth, cold and pain. A salient feature of PANs is that they are depolarized by GABA throughout adulthood. Primary afferent depolarization (PAD) produced by GABA released from interneurons located in spinal cord dorsal horn determines presynaptic inhibition, a pivotal mechanism in the gating and processing of somatosensory and nociceptive information in the spinal cord. PAD is due to Cl- efflux through GABAA receptor-channels. PAD amplitude and presynaptic inhibition are ultimately determined by [Cl-]i in PANs. Work originating in my lab established that the depolarizing action of GABA is possible because [Cl-]i in PANs is higher than predicted for electrochemical equilibrium due to Na+,K+,2 Cl- cotransporters, membrane proteins that actively accumulate Cl-. To study the function of these proteins we employ: 1) state-of-the-art-methods for measuring and manipulating intracellular ions using fluorescent probes and functional imaging microscopy, 2) freshly dissociated or cultured PANs, and 3) molecular methods.
2. Cellular and molecular mechanisms underlying cell volume control under normal and pathophysiological conditions in neurons and glial cells. We are currently focusing on the mechanisms underlying short-term changes in cell water volume and intracellular H+, Ca2+ and Cl- produced by exposure to ammonia (NH3) and ammonium (NH4+). These studies are important for understanding the pathophysiology of cellular brain edema that follows increased blood levels of NH3 and NH4+ (hyperammonemia) in humans with acute liver failure. Hyperammonemic brain edemas are a leading cause of mortality in patients with acute liver failure. We have developed in vitro models and optical methods for studying the pathophysiology of these edemas at the cellular and molecular levels.

Selected Publications

1. 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-London. 588(21):4089-4101 (2010).
2. Alvarez-Leefmans FJ 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). [Description]
3. 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). [Abstract]
4. 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. [Abstract]
5. Alvarez-Leefmans FJ. Neuronal landscapes. In homage to Santiago Ramon y Cajal. Rev Neurol. 45(11):703-703 (2007).
6. Munoz A, Mendez P, Defelipe J, Alvarez-Leefmans FJ. Cation-Chloride Cotransporters and GABA-ergic Innervation in the Human Epileptic Hippocampus. Epilepsia. 2007 Feb 21; [Epub ahead of print] [Abstract]
7. Alvarez-Leefmans FJ, Herrera-Pérez JJ, Márquez 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. [Abstract]
8. Hamann S, Herrera-Perez JJ, Bundgaard M, Alvarez-Leefmans FJ, Zeuthen T. Water permeability of Na+-K+-2Cl- cotransporters in mammalian epithelial cells. J Physiol. 568(Pt 1):123-135 (2005).
9. 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. [Abstract]
10. Hamann S, Kiilgaard JF, Litman T, Alvarez-Leefmans FJ, Winther BR, Zeuthen T. Measurement of cell volume changes by fluorescence self-quenching. J Fluoresc. 12(2):139-145 (2002).
11. 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. [Abstract]
12. 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. [Abstract]
13. Alvarez-Leefmans FJ. Intracellular Chloride Regulation. In: Cell Physiology Source Book. A Molecular Approach. (editor: N. Sperelakis).Third Edition. pp. 301-318. Academic Press, San Diego. 2001.
14. Alvarez-Leefmans FJ, Herrera-Perez JJ, Marquez MS, Blanco VM. Parallel changes in intracellular pH and cell water volume measured in single cells using the fluorescent probe BCECF. Journal of Physiology-London. 523:86P-87P (2000).
15. Alvarez-Leefmans FJ. Cellular and molecular biology of neural aging. Actual situation and perspectives. Salud Mental. 22(5):6-16 (1999).
16. Alvarez-Leefmans FJ, Boyarsky G, Marquez S. Changes in cell volume and pH(i) induced by ammonia and ammonium in neuroblastoma cells studied with fluorescent probes. Biophys J. 76(1):A203-A203 (1999).
17. Rosas VD, Boyarsky G, Marquez S, Alvarez-Leefmans FJ. Quantitative analysis of changes in cell volume and intracellular pH induced by ammonia and ammonium in neuroblastoma cells studied with fluorescent probes. J Gen Physiol. 14(1):30 (1999).
18. Altamirano J, Brodwick MS, Alvarez-Leefmans FJ. Regulatory volume decrease and intracellular Ca2+ in murine neuroblastoma cells studied with fluorescent probes. The Journal of General Physiology 112: 145-160, 1998. [Abstract]
19.  Cruzblanca H, Gamino SM, Bernal J, Alvarez-Leefmans FJ.Trifluoperazine enhancement of Ca2+-dependent inactivation of L-type Ca2+ currents in Helix aspersa neurons. Invert Neurosci. 1998;3(4):269-278.
20. Valverde MA, Bond TD, Hardy SP, et al. The multidrug resistance P-glycoprotein modulates cell regulatory volume decrease. EMBO J. 1996;15(17):4460-4468.
21. Crowe WE, Altamirano J, Huerto L, Alvarez-Leefmans FJ.Volume changes in single N1E-115 neuroblastoma cells measured with a fluorescent probe. Neuroscience. 1995;69(1):283-296.
22. Alvarez Leefmans FJ, Merediz Alonso G, Fernandez Calderon JR. The consequences of sodium pump inhibition in the neurons and its relevance to the physiopathology of the cell damage produced by anoxic ischemia]. Gac Med Mex. 1994;130(5):347-354.
23. Alvarez-Leefmans FJ, Cruzblanca H, Gamino SM, Altamirano J, Nani A, Reuss L. Transmembrane ion movements elicited by sodium pump inhibition in Helix aspersa neurons. J Neurophysiol. 1994;71(5):1787-1796.
24. Alvarez-Leefmans FJ,Gamino SM, Reuss L. Cell volume changes upon sodium pump inhibition in Helix aspersa neurones. J Physiol. 1992;458:603-619.
25. Alvarez-Leefmans FJ, Nogueron I. Intracellular chloride homeostasis in vertebrate nerve cells. Acta Physiol Scand Suppl. 1989;582:17.
26. Cruzblanca H, Alvarez-Leefmans FJ.The effect of temperature on electrical interactions between antidromically stimulated frog motoneurons and dorsal root afferent axons. Neuroscience. 1989;33(1):193-201.
27. Alvarez-Leefmans FJ,Gamino SM, Giraldez F, Nogueron I. Intracellular chloride regulation in amphibian dorsal root ganglion neurones studied with ion-selective microelectrodes. J Physiol. 1988;406:225-246.
28. Alvarez-Leefmans FJ, Giraldez F, Gamino SM. Intracellular free magnesium in excitable cells: its measurement and its biologic significance. Can J Physiol Pharmacol. 1987;65(5):915-925.