The long-term goal of our research is to understand the mechanisms by which ion channel-mediated calcium influx regulates cellular physiology. Currently, we focus on the role of TRP (transient receptor potential) channels, a superfamily of cation channels that are conserved from worms to humans and have been implicated in a number of human diseases. Our current understanding of the function and regulation of TRP channels primarily derives from in vitro studies performed in various cell culture systems;however, the roles of these channels in regulating cellular physiology in vivo, particularly in the context of whole organisms, have not been well evaluated. Here we propose to characterize the in vivo function and regulation of TRP channels in C. elegans, a genetically tractable model organism whose genome encodes all the seven TRP subfamilies, all of which are highly homologous to their vertebrate counterparts. We will focus on two groups of calcium-permeable TRP channels, TRPC and TRPN. As a first step, we have isolated genetic mutants of all the members in these two TRP subfamilies. We will characterize the defects of these trp mutants, and design a series of experiments aimed at elucidating the mechanisms by which these TRP channels regulate calcium signaling at the cellular and organismal level. We will also test some hypotheses with respect to the role of these TRP channels in regulating general calcium signaling. To do so, we will apply a multidisciplinary approach involving molecular genetics, cell biology, cellular imaging, electrophysiology and biochemistry. Given the high conservation of TRP family channels throughout phylogeny and the fact that mutations in TRP family channels lead to a number of human diseases such as polycystic kidney disease, familial focal segmental glomerulosclerosis and hypomagnesemia, the proposed studies may provide novel insights into our understanding of the role of TRP family channels in cellular physiology and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078276-05
Application #
7845083
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Rivera-Rentas, Alberto L
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$277,621
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physiology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Wescott, Seth A; Rauthan, Manish; Xu, X Z Shawn (2013) When a TRP goes bad: transient receptor potential channels in addiction. Life Sci 92:410-4
Singaravelu, Gunasekaran; Chatterjee, Indrani; Rahimi, Sina et al. (2012) The sperm surface localization of the TRP-3/SPE-41 Ca2+ -permeable channel depends on SPE-38 function in Caenorhabditis elegans. Dev Biol 365:376-83
Kang, Lijun; Wescott, Seth; Li, Wei et al. (2011) In touch - the molecular basis of mechanosensory transduction. Biochem (Lond) 33:18-20
Li, Wei; Kang, Lijun; Piggott, Beverly J et al. (2011) The neural circuits and sensory channels mediating harsh touch sensation in Caenorhabditis elegans. Nat Commun 2:315
Xiao, Rui; Xu, X Z Shawn (2011) C. elegans TRP channels. Adv Exp Med Biol 704:323-39
Wang, George J; Kang, Lijun; Kim, Julie E et al. (2010) GRLD-1 regulates cell-wide abundance of glutamate receptor through post-transcriptional regulation. Nat Neurosci 13:1489-95
Xiao, Rui; Xu, X Z Shawn (2010) Mechanosensitive channels: in touch with Piezo. Curr Biol 20:R936-8
Liu, Jie; Ward, Alex; Gao, Jingwei et al. (2010) C. elegans phototransduction requires a G protein-dependent cGMP pathway and a taste receptor homolog. Nat Neurosci 13:715-22
Kang, Lijun; Gao, Jingwei; Schafer, William R et al. (2010) C. elegans TRP family protein TRP-4 is a pore-forming subunit of a native mechanotransduction channel. Neuron 67:381-91
Ward, Alex; Walker, Vyvyca J; Feng, Zhaoyang et al. (2009) Cocaine modulates locomotion behavior in C. elegans. PLoS One 4:e5946

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