The objective of this proposal is to characterize a fundamental calcium signaling mechanism that regulates long lasting intracellular adaptive responses to light stimulation and, when abnormal, causes photoreceptor degeneration. We will determine how depletion of intracellular calcium stores triggers calcium influx through store-operated calcium channels in the plasma membrane of photoreceptors. The molecular isoforms of store-operated channels will be identified and their role in regulating the amplitude and frequency of spontaneous synaptic responses and light-evoked responses, determined. The mechanisms, through which pathological calcium influx through store-operated channels kills photoreceptors will be characterized in mouse model systems for inherited retinal degeneration and in mice lacking store-operated (TRPC) channel isoforms.
Two Specific Aims are proposed:
Specific Aim 1 : To characterize the roles of store-operated calcium channel entry in photoreceptor calcium homeostasis and neurotransmission Specific Aim 2: To identify expression of transient receptor potential channels (TRPCs) in the retina, and to determine their role in store-operated calcium entry and visual signaling The experiments in isolated cells, retinal slices and TRPC knockout mice will combine high-resolution calcium imaging techniques with patch clamp electrophysiology, immunocytochemistry, RT-PCR, gene chip and RNAi technology. Depletion of calcium stores and dysfunctional calcium influx kill photoreceptors. Thus, the proposed studies will help us understand how photoreceptors adjust their calcium levels to maintain optimal signaling range and will also help us identify potential candidate cellular targets for therapeutic interventions during retinal disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013870-09
Application #
8132340
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2002-03-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2011
Total Cost
$321,829
Indirect Cost
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Butler, Michael R; Ma, Hongwei; Yang, Fan et al. (2017) Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency. J Biol Chem 292:11189-11205
Molnár, Tünde; Yarishkin, Oleg; Iuso, Anthony et al. (2016) Store-Operated Calcium Entry in Müller Glia Is Controlled by Synergistic Activation of TRPC and Orai Channels. J Neurosci 36:3184-98
Barabas, Peter; Gorusupudi, Aruna; Bernstein, Paul S et al. (2016) Mouse Models of Stargardt 3 Dominant Macular Degeneration. Adv Exp Med Biol 854:137-43
Phuong, Tam T T; Yarishkin, Oleg; Križaj, David (2016) Subcellular propagation of calcium waves in Müller glia does not require autocrine/paracrine purinergic signaling. Channels (Austin) 10:421-427
Križaj, David (2016) Polymodal Sensory Integration in Retinal Ganglion Cells. Adv Exp Med Biol 854:693-8
Ryskamp, Daniel A; Iuso, Anthony; Križaj, David (2015) TRPV4 links inflammatory signaling and neuroglial swelling. Channels (Austin) 9:70-2
Cahoon, Judd M; Rai, Ruju R; Carroll, Lara S et al. (2015) Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy. Diabetes 64:4247-59
Deering-Rice, Cassandra E; Mitchell, Virginia K; Romero, Erin G et al. (2014) Drofenine: A 2-APB Analogue with Greater Selectivity for Human TRPV3. Pharmacol Res Perspect 2:e00062
Ryskamp, Daniel A; Redmon, Sarah; Jo, Andrew O et al. (2014) TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision. Cells 3:914-38
Chen, Minghui; Križaj, David; Thoreson, Wallace B (2014) Intracellular calcium stores drive slow non-ribbon vesicle release from rod photoreceptors. Front Cell Neurosci 8:20

Showing the most recent 10 out of 38 publications