Cellular excitability influences essentially every aspect
of life, from fertilization to breathing and heart beating. The
major interests of the lab concern the regulation of cellular excitability,
neuronal network activity and animal behavior by ion channels,
G-protein coupled receptors, tyrosine kinases and calcium signaling.
A
recent focus in the lab is to study the molecular mechanism of
neuronal excitability control by extracelular ions (with emphasis
on Ca2+ and Na+) and peptide neurotransmitters. Significant changes
in extracellular Ca2+ concentrations ([Ca2+]e) can happen in certain
brain areas during physiological and pathological conditions such
as seizures and brain ischemia. Unlike Na+ and K+, extracellular
Ca2+ generally controls neuronal excitability in a “negative” manner:
decrease in [Ca2+]e normally excites neurons and increase in [Ca2+]e
suppresses neurons. We are interested in understanding at the molecular
level how neurons sense the [Ca2+]e changes, how the information
is transmitted to the intracellular second messenger system, and
how neuronal circuit function is affected. Numerous neuropeptides
are used by the nervous systems as chemical signals to regulate
physiological processes such as feeding, rewarding, pain sensation,
arousal and wakefulness. We are interested in how several neuropeptides
influence the electrical properties of individual neurons in various
brain regions and spinal cord. Along this line, we discovered a
novel ion channel activation mechanism by G-protein coupled receptors:
it is independent of G-protein activation but requires the Src
family of tyrosine kinases and a largely uncharacterized protein
mUNC-80 (see Lu et al. (2008)). Current efforts in this project
focus on uncovering how the receptor activation and channel opening
is coupled and whether such signaling events might shape neuronal
circuit plasticity involved in physiological/pathophysiological.
Another
area of research in the lab concerns rhythm generation. All animals
display long-period rhythmic behaviors such as circadian
rhythm (~ 24 hours), as well as ones with shorter periods such
as locomotion, heart beating, and breathing (milliseconds to seconds).
We are interested in the molecular mechanisms underlying the generation
and modulation of the “short-period” rhythms (see Lu
et al. (2007)).
We use an integrative approach to study the physiological
problems. At the molecular level, we use molecular biology, protein
chemistry
and bioinformatics to clone and purify channel proteins and their
associated partners. We use electrophysiology methods to record
the electrical activities from a single molecule (single channel
recording), a whole cell, or a nerve bundle. At the cellular
level, we use immunochemstry to determine protein localization
and fluorescence
microcopy to image Ca2+ dynamics inside the cells. At the systems
level, we modify the genomes of animals (usually in the mice
using homologous recombination in embryonic stem cells) and study
the
consequences of such modifications on whole animal physiology
and behavior.
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