The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision

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Abstract

Calcium (Ca²⁺) plays an important role in the function and health of neurons. In vertebrate cone photoreceptors, Ca²⁺ controls photoresponse sensitivity, kinetics, and light adaptation. Despite the critical role of Ca²⁺ in supporting the function and survival of cones, the mechanism for its extrusion from cone outer segments is not well understood. Here, we show that the Na⁺/Ca²⁺, K⁺ exchanger NCKX4 is expressed in zebrafish, mouse, and primate cones. Functional analysis of NCKX4-deficient mouse cones revealed that this exchanger is essential for the wide operating range and high temporal resolution of cone-mediated vision. We show that NCKX4 shapes the cone photoresponse together with the cone-specific NCKX2: NCKX4 acts early to limit response amplitude, while NCKX2 acts late to further accelerate response recovery. The regulation of Ca²⁺ by NCKX4 in cones is a novel mechanism that supports their ability to function as daytime photoreceptors and promotes their survival.

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Frans Vinberg

Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.
Tian Wang

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Alicia De Maria

Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.
Haiqing Zhao

Department of Biology, Johns Hopkins University, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Steven Bassnett

Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, United States

Competing interests
The authors declare that no competing interests exist.
Jeannie Chen

Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, United States

For correspondence
jeannie@med.usc.edu

Competing interests
The authors declare that no competing interests exist.
Vladimir J Kefalov

Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, United States

For correspondence
Kefalov@vision.wustl.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1659-008X

Funding

National Eye Institute (EY019312 EY025696 EY012155 EY026651)

Frans Vinberg
Tian Wang
Alicia De Maria
Steven Bassnett
Jeannie Chen
Vladimir J Kefalov

Research to Prevent Blindness

Frans Vinberg
Alicia De Maria
Steven Bassnett
Vladimir J Kefalov

Ella ja Georg Ehrnroothin Säätiö

Frans Vinberg

National Institute on Deafness and Other Communication Disorders (DC007395)

Haiqing Zhao

National Eye Institute (EY027387)

Jeannie Chen
Vladimir J Kefalov

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#A-3381-01) of the University of Washington in St. Louis..

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.