department of biology & program in neuroscience
:: current lab personnel ::
:: lab alumni ::
We are a molecular pharmacology lab with a
research focus on the structure and function of the gamma-aminobutyric acid
type A (GABA(A)) receptor, the major inhibitory neurotransmitter receptor in
the mammalian brain. This receptor is also a target for several classes
of anxiolytics, hypnotics, and anesthetics, all of whom work to allosterically
modulate inhibitory tone in the central nervous system. We are
interested in defining structure and dynamics of the binding sites for several
synthetic and naturally occuring modulators of the GABA(A) receptor.
Research arena #1 :: Mapping the binding pocket for pregnane neurosteroids
Anxiety is a profound dysregulation in the homeostatic control of emotion in the brain. Although the parts of the brain involved in short and long term anxiety have been identified, the molecular underpinnings of anxiety are still largely unknown. Mood changes accompanying stress, birth, and the menstrual cycle are thought to be driven by dynamic changes in steroid levels in the brain. These steroids, including allopregnanolone (ALLO), the primary metabolite of progesterone, exert their effects by binding to the GABA(A) receptor. Low circulating levels of progesterone are thought to underlie the anxiety evoked during premenstrual syndrome, post-partum depression, and post-traumatic stress disorder. Understanding the molecular action of progesterone on the GABA(A) receptor will yield new information about how the brain controls and prevents the dysregulations accompanying anxiety.
We are interested in
mapping the steroid binding site on the GABA(A) receptor. Our initial
approach has used chimeragenesis to more deeply understand the selectivity of
ALLO for the GABA(A) receptor over other members of the ligand-gated ion
channel superfamily. We are using two-electrode voltage clamping to
functionally assess each chimera in order to define some of the amino acids
that are necessary for ALLO binding and/or allosteric modulation.
Understanding this selectivity and resolving the structure of this binding
pocket will help us understand how steroids dynamically regulate anxiety in
the brain and may result in the rational design of drugs to control anxiety.
Research arena #2 :: Resolving the molecular action of naturally-occuring anxiolytics
A growing body of literature suggests that kava root (Piper methysticum) extracts, used by Pacific Islanders for their anxiolytic and sedating properties, modulate inhibitory neurotransmitter receptors in the central nervous system. Recent evidence suggests that many herbal extracts that promote the reduction of anxiety and/or sedation bind to and modulate the GABA(A) receptor, including thymol, (+)-menthol, thujone, and extracts of Gingko biloba, St. John’s Wort (Hypericum), and Scutellaria baicalensis Georgi. At present, the molecular target(s) of kava root extracts remain unknown. In collaboration with John Gillespie ’05 (see personnel), we uncovered a few studies within the “dusty backroads” of molecular pharmacology that suggested that kavalactones can bind to the GABA(A) receptor. We have developed an ongoing project in the laboratory to (a) obtain and subclone multiple isoforms of the GABA(A) receptor for oocyte expression, (b) obtain several putatively neuroactive kavalactones, and (c) look for physiological sensitivity among our library of GABA(A) receptors to various kavalactones. Understanding the sensitivity of the GABA(A) receptor to naturally-occuring anxiolytics may revolutionize the current clinical treatment paradigm for anxiety management.