Areas of Interest
We are interested in Ca2+ signaling mechanisms and their
potential roles under physiological and pathological conditions.
Calcium is the most common signal transduction element in
virtually all cells ranging from bacteria to neurons. Recent
studies have demonstrated the importance of transient receptor
potential (TRP) channels in mediating calcium signals. The
mammalian TRP channel superfamily consists of a diverse group of
Ca2+ permeable nonselective cation channels that may play a role
in pain transduction, thermo-sensation, mechanotransduction,
tumor suppression, vasodilatation, and neurodegenerative
disorder. More than 25 mammalian TRP channel genes have been
cloned since the first TRP channel protein was identified in
Drosophila, yet their physiological functions are to be
revealed.
We apply a multi-disciplinary approach to study the potential
physiological and pathological functions of the Ca2+-permeable
TRP channels. We use molecular biology and biochemistry
approaches to identify channel proteins and the associated
partners; we use patch-clamp to study channel functions and
gating mechanisms; and we use in vivo animal models with
disrupted or modified channel genes to investigate physiological
or pathological functions of the TRP channels.
We currently focus on two major projects. First, we will
investigate TRP channels and Ca2+ signaling mechanisms in
cardiac fibrogenesis. Cardiac fibrosis is detrimental and is
associated with a variety of heart diseases including
arrhythmia, hypertrophy, and heart failure. However, Ca2+
signaling mechanism in cardiac fibrogenesis is unknown. This
project will reveal potential roles of TRP channels in mediating
Ca2+ signals in the cardiac fibroblast’s proliferation,
differentiation, and fibrogenesis. Second, we are interested in
the gating mechanisms and physiological functions of TRPM7 and
TRPM6, the two channel-kinase proteins that exhibit both channel
functions and protein kinase activities.
Lab Rotation Projects
Project #1: Potential physiological functions of
TRPM7. We have recently found that TRPM7 is abundantly expressed
in the heart (Nat. Cell. Biol. 2002). The goal of this project
is to study how TRPM7 contributes to cardiac fibrogenesis, a
pathological process that is involved in a variety of heart
diseases including hypertrophy, heart failure and sudden cardiac
death. For this project, the rotation student will start with
studying how TRPM7 affects cardiac fibroblasts’ proliferation
and differentiation.
Project #2: Gating mechanisms of TRPM7. A recent study
showed that TRPM7 is responsible for neuronal cell death caused
by anoxia. We have found that TRPM7 activity can be dramatically
potentiated by ischemia related conditions (JGP, 2005. in
press). This project is to identify the amino acid residues
which determine the permeability, selectivity and gating
mechanisms of TRPM7. Recombinant TRPM7 will be expressed in
over-expression system and site-directed mutagenesis will be
applied in this study. The ultimate goal of this project is to
reveal the mechanism by which TRPM7 contributes to ischemic
neuronal cell death and stroke.
Project #3: TRPV6 and Ca2+ signaling mechanism. TRPV6
(or CaT1) is the most Ca2+ selective ion channel in the TRP
superfamily (Nature, 2001). Activation of TRPV6 requires lowered
intracellular Ca2+ concentration. The objective of this project
is to study how TRPM6 is gated under physiological conditions
and potential roles of TRPV6 in Ca2+ signaling mechanism.
Looking for interacting proteins with TRPV6 will be the first
step for this project.
Selected Publications
Du J, Xie J, Yue L. Intracellular calcium activates TRPM2 and
its alternative spliced isoforms. Proc Natl Acad Sci U S A.
2009; 107 (17) 1239-44.
Li M, Du J, Jiang J, Ratzan W, Su L-T, Runnels LW, Yue L.
Molecular Determinants of Mg2+ and Ca2+ Permeability and pH
Sensitivity in TRPM6 and TRPM7. J. Biol. Chem. 2007;
282(35):25817-25830.
Li M, Jiang J, Yue L. Functional characterization of homo- and
heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol. 2006
May;127(5):525-37.
Su L, Agapito M, Li, Simpson W, Huttenlocher A, Habas R, Yue L,
Runnel R. TRPM7 regulates cell adhesion by controlling the
calcium-dependent protease calpain. J Biol Chem. 2006 Apr
21;281(16):11260-70. Epub 2006 Jan 25.
Jiang J, Li M, Yue L. Potentiation of TRPM7 inward currents by
acidosis. Journal of General Physiology. 2005; 126 (2) 137-150.
Dessaint J, Yu W, Krause JE, Yue L. Yohimbine inhibits firing
activities of rat dorsal root ganglion neurons by blocking Na+
channels and vanilloid VR1 receptors. Eur J Pharmacol. 2004;
6:485(1-3):11-20.
*Runnels L, *Yue L, Clapham D. The TRP-PLIK channel is
inactivated by PIP2 hydrolysis. Nature Cell Biology. 2002;
4(5):329-36. *Co-first author
Yue L, Navarro B, Ren D, Clapham D. The cation selectivity
filter of the bacterial sodium channel, NaChBac. Journal of
General Physiology. 2002; 120 (6): 845-53.
Yue L, Peng J-B, Hediger M A, Clapham D.E. CaT1 Manifests the
pore properties of the calcium release activated calcium
channel. Nature. 2001; 410, 705 – 709. [see News and Views.
Nature 2001 410:648-9].
*Ren D, *Navarro B, *Xu H, *Yue L, Shi Q, Clapham. A
prokaryotic voltage-gated sodium channel. Science. 2001;
294(5550):2372-5. [see News and Views. Science 2001 294:
2306-2308]. *Co-first author.
Runnels L, Yue L, Clapham D. TRP-PLIK, a bifunctional protein
with kinase and ion channel activities (Originally published in
Science Express as 10.1126/science.1058519 on January 18, 2001).
Science. 2001;291 (5506): 1043-1047.
Yue L, Wang Z, Rindt H, Nattel S. Molecular evidence for a
role of Shaw (Kv3) potassium channel subunits in potassium
currents of dog atrium. Journal of Physiology. 2000; 527 (3):
467-478.
Yue L, Feng J, Wang Z, Nattel S. Effects of ambasilide,
quinidine, flecainide and verapamil on ultra-rapid delayed
rectifier potassium currents in canine atrial myocytes.
Cardiovasc Res. 2000 Apr;46(1):151-61.
Nattel S, Li D, Yue L. "Basic mechanisms of atrial
fibrillation-very new insights into very old ideas. Annual
Review of Physiology. 2000; 62: 51-77.
Nattel S, Matthews C, De Blasio E, Han W, Li D, Yue, L.
Dose-dependence of 4-aminopyride concentrations and
electrophysiological effects in dogs: potential relevance to
ionic mechanisms in vivo. Circulation. 2000; 101 (10):
1179-1184. rev. 6-09 |
