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 is funded by NIH and involves two tightly linked
areas:
- 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.
- 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:
- 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]
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Alvarez-Leefmans
FJ, Nani A, Márquez S. Chloride transport, osmotic
balance and presynaptic inhibition. In: Presynaptic Inhibition and
Neural Control (P. Rudomín, R. Romo and L. Mendell, eds). Oxford
University Press. New York pp. 50-79, 1998.
- Alvarez-Leefmans
FJ, Gamiño SM, Giraldez F, Noguerón I. Intracellular
chloride regulation in amphibian dorsal root ganglion neurones studied
with ion-selective microelectrodes. Journal of Physiology (London)
406:225-246; 1988.
For more information, contact:
Francisco J. Alvarez-Leefmans, M.D., Ph.D.
Professor
Department of Pharmacology and Toxicology
Boonshoft School of Medicine
Wright State University
3640 Colonel Glenn Hwy.
Dayton, OH 45435-0001
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