About the Book The importance of chloride ions in cell physiology has not been fully recognized until recently, in spite of the fact that chloride (Cl-), together with bicarbonate, is the most abundant free anion in animal cells, and performs or determines fundamental biological functions in all tissues. For many years it was thought that Cl- was distributed in thermodynamic equilibrium across the plasma membrane of most cells. Research carried out during the last couple of decades has led to a dramatic change in this simplistic view. We now know that most animal cells, neurons included, exhibit a non-equilibrium distribution of Cl- across their plasma membranes. Over the last 10 to 15 years, with the growth of molecular biology and the advent of new optical methods, an enormous amount of exciting new information has become available on the molecular structure and function of Cl- channels and carriers. In nerve cells, Cl- channels and carriers play key functional roles in GABA- and glycine-mediated synaptic inhibition, neuronal growth and development, extracellular potassium scavenging, sensory-transduction, neurotransmitter uptake and cell volume control. Disruption of Cl- homeostasis in neurons underlies pathological conditions such as epilepsy, deafness, imbalance, brain edema and ischemia, pain and neurogenic inflammation. This book is about how chloride ions are regulated and how they cross the plasma membrane of neurons. It spans from molecular structure and function of carriers and channels involved in Cl- transport to their role in various diseases.
Alvarez-Leefmans, F. Javier: - Research Interests Research in his 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, they 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+ scavenging. 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 their lab, and are used in conjunction with molecular methods, knockout models, and several microanatomical techniques. Their current research involves two projects: 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. 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.
Delpire, Eric: - Dr. Eric Delpire teaches at the Vanderbilt University, Nashville, USA
