The goal of this work is to better understand how auxiliary alpha2delta subunits modulate neuronal voltage-gated calcium channels (VGCCs) which affect neuronal migration (Komuro, et. al,1998), synaptogenesis (Bahls, et. al., 1998), and neurotransmission (Dunlap, 1995). Neuronal VGCCs consist of an alpha1 pore subunit and auxiliary subunits, alpha2delta, beta, and possibly gamma, which differentially regulate channel properties (Catterall, 2000). Studies in heterologous expression systems suggest that alpha2delta subunits associate with alpha1 and modulate channel function by altering the membrane trafficking and biophysical properties of VGCCs (Klugbauer, et. al, 2003). However, the in vivo function of alpha2delta in regulating pore-forming alpha1 subunits is less clear. Several straightjacket (stj) mutants with genetic lesions in the Drosophila alpha2delta subunit have been isolated. Initial electrophysiological and EM studies of stj mutants hint at defects in vesicle fusion. I propose to study the in vivo function of Drosophila alpha2delta, focusing on its role in regulating neuronal VGCCs and neurotransmission. Initially, I will generate null alleles of alpha2delta to aid in the genetic characterization of isolated mutations. I will then investigate VGCC trafficking in stj mutants using a fluorescent-tagged alpha1 pore subunit. In addition, I will determine whether alpha2delta modulates channel function using calcium imaging. Finally, I will explore whether interactions between alpha2delta and beta are necessary for proper VGCC function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30NS056520-02
Application #
7246456
Study Section
Special Emphasis Panel (ZNS1-SRB-M (34))
Program Officer
Silberberg, Shai D
Project Start
2006-07-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$29,113
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Yao, Chi-Kuang; Lin, Yong Qi; Ly, Cindy V et al. (2009) A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis. Cell 138:947-60
Ly, Cindy V; Yao, Chi-Kuang; Verstreken, Patrik et al. (2008) straightjacket is required for the synaptic stabilization of cacophony, a voltage-gated calcium channel alpha1 subunit. J Cell Biol 181:157-70