Vertebrate photoreceptors are an elegant example of form being finely tuned to support function. These primary sensory neurons are linearly organized into a series of morphologically and functionally distinct compartments. All of the compartments contribute in different ways to the maintenance and signaling activity of this neuron. For instance, photons are captured in the outer segment, the synapse communicates that event to downstream neurons, and the inner segment, typically thought of as the housekeeping compartment, houses the ion channels, pumps, and transporters needed to set and maintain the circulating current that is ultimately used to communicate the presence or absence of light. The polarized trafficking of select ion channels to the different photoreceptor compartments is well recognized as essential for the health and function of this cell. Yet, the mechanisms controlling the subcellular trafficking and localization of ion channels in this cell or for that matter, most others, is poorly understood at best. The overarching goal of this project is to identify the mechanisms that control polarized protein trafficking in photoreceptors. In this proposal we are building on the knowledge we gained in our earlier studies of HCN1, a hyperpolarization activated channel that filters light responses and is essential for vision in bright light.
Aim 1 probes how the assembly status and permissiveness of HCN1 to leave the ER is coordinated.
This aim also tests if the mechanisms controlling HCN1 processing are used to regulate Kv2.1/Kv8.2, a related ion channel also found within the inner segment that when absent results in aberrant signaling and cone dystrophy.
Aim 2 probes the function and mechanism of a second trafficking signal within HCN1 that we propose is required, at least in part, to recruit the protein coat needed for the generation of HCN1-bearing transport vesicles. A suite of genetic, biochemical, imaging, and physiological tools are used. Altogether, this work will reveal fundamental mechanisms used in the polarized trafficking of photoreceptor proteins, shed light on the contributions made by the early secretory pathway to the regulation of ion channels, and is anticipated to transform current views of the fundamental organization of photoreceptors in health and disease.

Public Health Relevance

In this proposal we will investigate how the meticulously distinct distribution of proteins found in photoreceptors is controlled. Results of this work will reveal fundamental aspects of photoreceptor biology and has the potential to illuminate new strategies to slow, halt, or reverse blindness.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY020542-08
Application #
9414597
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Neuhold, Lisa
Project Start
2010-04-01
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Iowa
Department
Biochemistry
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Pan, Yuan; Laird, Joseph G; Yamaguchi, David M et al. (2015) An N-Terminal ER Export Signal Facilitates the Plasma Membrane Targeting of HCN1 Channels in Photoreceptors. Invest Ophthalmol Vis Sci 56:3514-21
Cao, Yan; Sarria, Ignacio; Fehlhaber, Katherine E et al. (2015) Mechanism for Selective Synaptic Wiring of Rod Photoreceptors into the Retinal Circuitry and Its Role in Vision. Neuron 87:1248-1260
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Pan, Yuan; Laird, Joseph G; Yamaguchi, David M et al. (2015) A di-arginine ER retention signal regulates trafficking of HCN1 channels from the early secretory pathway to the plasma membrane. Cell Mol Life Sci 72:833-43
Pan, Yuan; Bhattarai, Sajag; Modestou, Modestos et al. (2014) TRIP8b is required for maximal expression of HCN1 in the mouse retina. PLoS One 9:e85850
Pearring, Jillian N; Lieu, Eric C; Winter, Joan R et al. (2014) R9AP targeting to rod outer segments is independent of rhodopsin and is guided by the SNARE homology domain. Mol Biol Cell 25:2644-9
Liu, Xiaoni; Kerov, Vasily; Haeseleer, Fran├žoise et al. (2013) Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2. Channels (Austin) 7:514-23
Baker, Sheila A; Kerov, Vasily (2013) Photoreceptor inner and outer segments. Curr Top Membr 72:231-65
Knoflach, Dagmar; Kerov, Vasily; Sartori, Simone B et al. (2013) Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2. Channels (Austin) 7:503-13

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