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Developmental biology - Sight

Molecular Pit Crew Continuously Refuels Retinal Cells

How we see may be due to continuous molecular refueling of retinal cell membranes...


During Indy Car races, pit crews refuel, replace wheels, make minor repairs all within seconds. People working in a highly coordinated manner are extraordinarily efficient. But molecular efficiency and coordination surpasses any pit crew. For example, when light hits our retina - millions of signals begin a molecular cascade within a millisecond. At that rate, retinal cells could run out of signaling molecules within seconds. However, cells process at incredible speed, rapidly forming new molecules and keeping retinal cells continually signaling.

After studying this phenomenon for more than a decade, Raghu Padinjat Md, PhD and his team have identified a set of three proteins responsible for the efficient operation of the retinal pathway. The enzyme PI4KIIIa (phosphatidylinositol 4-kinase IIIa), along with the little known proteins Efr3 and TTC7, are crucial to maintaining the lipid molecule PIP2 on retinal surface membranes to produce continuous cell signaling.
The phospholipase C (PLC) pathway is a widely occurring signaling system in cells and used to relay information in response to stimuli by hormones, neurotransmitters - even odors and light. For example, in the eyes, light falling on the surface membranes of retinal cells activates membrane-bound PLC which splits PIP2 into secondary messengers that transfer information to cells - the very first step in the signaling cascade that feeds into our sense of vision.

During signaling, PIP2 pools on the retinal surface membrane and is rapidly used up. A constant resupply of PIP2 is needed to maintain retinal signaling. A surface membrane level of PI4P (phosphatidylinositol 4 phosphate) is also crucial as PI4P is a key precursor to PIP2 synthesis. PI4P is in turn synthesized by phosphatidylinositol kinases or PI4Ks, which has 3 other known forms - PI4KIIIa, PI4KIIIa, and PI4KIIa.
Using the fruit fly, Drosophila, as a model system, Padinjat's team found that the enzyme PI4KIIIa is the isoform maintaining PI4P levels during cell signaling. Mutant flies with very low levels of this enzyme in their eyes show a very reduced response to light. This PI4KIIIa deficiency is due to the depletion of PIP2 on the surface membranes of that fly's retinal cells - confirming the vital role of PI4KIIIa in maintaining PIP2 levels. The study also found how PI4KIIIa works in conjunction with two other proteins, Efr3 and TTC7, to maintain PI4P levels.

Much like the pit crew refueling cars during a race, Efr3, TTC7, and PI4KIIIa function together to rapidly refuel signaling cells with PIP2 and keep retinal signaling going. Future work will focus on understanding how these 3 enzymes replenish PI4P and PIP2 levels during cell signaling. The work is published in the Journal of Cell Science.

"Genetic variations in one of the components of the Efr3 complex, and is linked to autism spectrum disorders in humans. Finding out that PI4KIIIa helps maintain surface-membrane PIP2 levels, fills a major gap in our understanding of PIP2 metabolism and PLC signaling. As the two processes are highly conserved across organisms occurring in many cell types, our work in flies can actually tell us a lot about these pathways in human cells." adds Raghu Padinjat.

Abstract
The activation of phospholipase C (PLC) is a conserved mechanism of receptor activated cell signaling at the plasma membrane. PLC hydrolyzes the minor membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and continued signaling requires the resynthesis and availability of PI(4,5)P2 at the plasma membrane. PI(4,5)P2 is synthesized by the phosphorylation of phosphatidylinositol-4-phosphate (PI4P). Thus, a continuous supply of PI4P is essential to support ongoing PLC signaling. While the enzyme PI4KA has been identified to perform this function in cultured mammalian cells, its function in the context of an in vivo physiological model has not been established. In this study, we show that in Drosophila photoreceptors, PI4KIIIa activity is required to support signaling during G-protein coupled PLC activation. Depletion of PI4KIIIa results in impaired electrical responses to light and reduced plasma membrane levels of PI4P and PI(4,5)P2. Depletion of conserved proteins Efr3 and TTC7 that assemble PI4KIIIa at the plasma membrane also results in an impaired light response and reduced plasma membrane PI4P and PI(4,5)P2 levels. Thus PI4KIIIa activity at the plasma membrane generates PI4P and supports PI(4,5)P2 levels during receptor activated PLC signaling.

Authors: Sruthi S. Balakrishnan, Urbashi Basu, Dhananjay Shinde, Rajan Thakur, Manish Jaiswal, and Padinjat Raghu.


Funding
This work was supported by the National Centre for Biological Sciences - TIFR. R.P. is supported by a Wellcome Trust-DBT India Alliance Senior Fellowship (IA/S/14/2/501540). U.B. was supported by a fellowship from the Council for Scientific and Industrial Research, India. M.J. is supported by Tata Institute of Fundamental Research and Ramaligaswami Re-Entry Fellowship DBT India (BT/RLF/Re-Entry/06/2016). Deposited in PMC for release after 6 months.


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Aug 31, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Photoreceptors (PINK) in fruit fly retinal cells that amplify cell signals.
Image Credit: Padinjat Raghu MD, PhD.


Phospholid by Wikipedia