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Channelopathies: Summary of the hot topic keynotes session
Magby, J. P., A. P. Neal, W. D. Atchison, I. P. Pessah, AND T. SHAFER. Channelopathies: Summary of the hot topic keynotes session. NEUROTOXICOLOGY. Intox Press, Inc, Little Rock, AR, 32(5):661-5, (2011).
The "Hot Topic Keynotes: Channelopathies" session of the 26th International Neurotoxicology Conference brought together toxicologists studying interactions of environmental toxicants with ion channels, to review the state of the science of channelopathies and to discuss the potential for interactions between environmental exposures and channelopathies. This session presented an overview of chemicals altering ion channel function and background about different channelopathy models. It then explored the available evidence that individuals with channelopathies may or may not be more sensitive to effects of chemicals. Dr. Tim Shafer began his presentation by defining what channelopathies are and presenting several examples of channelopathies. Channelopathies are mutations that alter the function of ion channels such that they result in clinically-definable syndromes including forms of epilepsy, migraine headache, ataxia and other neurological and cardiac syndromes (Kullmann, 2010). Because of the ubiquitous but heterogeneous nature of ion channels, channelopathy syndromes are highly variable, and depend not only on the type of channel mutated but also on how the mutation alters the function of the channel (Waxman, 2007). While there are a number of possible phenotypes resulting from channel mutations, one feature shared by a number of channelopathies is that they cause periodic and discrete attacks, allowing the carrier of the mutation to function normally between attacks (Kullmann, 2010). Like many genetic diseases, channelopathies tend to present early in life; some only cause dysfunction during development, others may continue to cause problems throughout life while others do not present overt (or at least recognized) clinical signs without environmental triggers (Pessah et al., 2010, Striessnig et al., 2010). In order to understand the full implications of these mutations, and their highly variable manifestations, it is essential to understand ion channel physiology and function. Ion channels are found in all cell types throughout the body, and have a wide variety of structures and functions. Ion channels serve as transmembrane pores that, when open, allow ions to pass across a membrane. Because movement of ions across a membrane results in electrical currents, ion channels serve essential functions in electrically excitable tissues, such as neural cells and cardiac, skeletal and smooth muscle. The opening and closing (gating) of ion channels is controlled either by changes in membrane potential( voltage (Vacher et al., 2008)), or by the binding of ligands such as neurotransmitters. Thus, ion channels typically are classified into one of two large groups based on the stimuli that activate them: voltage-gated or ligand gated. The voltage-gated ion channel family includes voltage-gated sodium channels, voltage-gated calcium channels, and voltage-gated potassium channels. All of these channels consist of a pore-forming a subunit and associated auxiliary subunits that modify the function and/or expression of the a subunit. Mutations in either the pore forming a subunit or the auxiliary subunits can manifest as clinical syndromes. Voltagegated sodium channels (VGSC) are responsible for neuronal depolarization as well as initiation and propagation of action potentials in the nervous system. Sodium channel mutations in humans and animals result in seizures, rare forms of familial migraine headache, movement and pain disorders (Catterall, 2000). The voltage-gated calcium channels (VGCC) are essential to cell signaling, neurotransmitter release and neuronal plasticity. Mutations in VGCC channels result in seizures, migraine, neurodegenerative disorders and myasthenic syndromes (Striessnig et al., 2010).
This session presented an overview of chemicals altering ion channel function and background about different channelopathy models. It then explored the available evidence that individuals with channelopathies may or may not be more sensitive to effects of chemicals.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
SYSTEMS BIOLOGY BRANCH