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Membrane Receptors and Transporters: Mechanisms and Roles in Human Diseases

Research Summary

Hui Sun uses a variety of techniques to uncover the mechanisms of membrane receptors and transporters implicated in human diseases. He hopes to use this knowledge to develop novel therapies for some still incurable diseases.

Vitamin A's multitasking ability has been an ongoing surprise to biologists, starting almost a century ago. Although best known for its essential role in vision, vitamin A performs diverse biological functions, such as morphogenic signaling in embryonic development, maintenance of immune competence, and regulation of neuronal signaling in the brain. The chemical basis of this versatility is the result of transformation of vitamin A into a group of compounds, known as retinoids, that differ in their configuration of double bonds, their oxidation state, and other modifications. It is well known that the eye contains a large amount of retinoids, but it is less well known that the brain is literally soaked in retinoids. When opsins, the light-absorbing proteins that rely on vitamin A––derived chromophore, are expressed in different regions of the brain in the novel optogenetics technique to study neural circuits, they effectively become light sensitive. But how is vitamin A efficiently delivered to the brain across the blood-brain barrier?

Under physiological conditions, virtually all vitamin A in the blood is not in its free form but bound to its high-affinity carrier protein. If this carrier protein is like a boat that carries vitamin A, how does it know when to unload its cargo? It was proposed more than 30 years ago that a cell-surface receptor exists that specifically binds to the carrier protein and mediates vitamin A uptake. By developing a new strategy, we identified this receptor as a multitransmembrane protein of previously unknown function. This receptor, which represents a new class of membrane transport protein, is clearly distinct from those involved in the transport of soluble ligands such as salt, water, and amino acids. Its function is analogous to a loading dock and, surprisingly, performs both the docking and unloading functions without using cellular energy. We are using a variety of techniques to study this membrane transport mechanism.

Retinoid can diffuse systemically, as demonstrated by retinoid drugs such as tretinoin and isotretinoin. Our body needs to synthesize one carrier protein just to deliver one molecule of vitamin A. Why did evolution come up with such a complicated mechanism to deliver vitamin A, when it might be achieved through the much simpler method of random diffusion? Like many essential things in life (e.g., water), humans cannot live without sufficient vitamin A, but too much of it can be detrimental, as demonstrated by the well-known toxicities associated with retinoid-based drugs. A targeted delivery and uptake system makes it possible to achieve precise and sufficient delivery to cells or organs that depend on retinoids, and, at the same time, avoid random and excessive uptake, which can lead to serious short-term or long-term toxicity. If vitamin A is viewed as a "drug" that is essential for the proper functioning of many human organs, then this is an ideal drug delivery system because it combines sustained release with targeted delivery. This system avoids the need for constant intake and minimizes "side effects" associated with random diffusion. Human genetic studies have identified mutations in this receptor that cause wide-ranging pathological phenotypes, including mental retardation, anophthalmia, congenital heart defects, and lung hypoplasia. These mutations abolish the vitamin A uptake activity of the receptor, and their severe pathological phenotypes illustrate the consequences of inactivating this cellular vitamin A uptake system.

Because of their potent biological activities, retinoids play positive or negative roles in many pathological conditions, such as visual disorders, cancer, infectious diseases, neurological disorders, diabetes, birth defects, and skin diseases. Retinoids have long been used to treat human skin diseases and cancer, but an excess level of retinoid is known to cause serious or even life-threatening side effects. These side effects illustrate the pathological consequences of overriding or bypassing the natural delivery system. The balance between sufficiency and excess also applies to the receptor responsible for vitamin A uptake. While the loss of the receptor causes severe pathological phenotypes, as demonstrated by human genetic studies, increased receptor levels have also been linked to pathological conditions such as cancer. The receptor is overexpressed more than 100-fold in certain cancer cells. We are studying the molecular mechanism underlying the regulation of cellular vitamin A uptake under physiological conditions, and how this regulation ensures sufficient but not excessive vitamin A uptake. These studies will shed light not only on the physiological mechanism of retinoid homeostasis but also on the pathological mechanisms of human diseases caused by insufficient or excessive retinoid levels.

We are also interested in employing a new technical strategy (and variations of it) that we have developed to identify medically important membrane receptors involved in cellular signaling that have not been identified by existing techniques. We have spent the past few years optimizing this strategy to expand our ability to detect and identify ligand/receptor complexes that are expressed at exceedingly low levels on the cell surface. Signaling receptors are analogous to antennas that receive and transmit signals. It is largely through receptors that extracellular signals guide cellular behaviors. To avoid confusion in complex physiological systems, evolution tends to come up with specific receptors for specific signals. For this reason, specific treatments for human diseases often change cellular behaviors by activating or inactivating receptors, as demonstrated by a large number of medically successful drugs. Our long-term goal is to uncover new receptor signaling mechanisms and to develop new therapeutic strategies based on the mechanisms.

A grant from the National Institutes of Health provided support for the study of the cellular mechanism of vitamin A uptake.

As of May 30, 2012

Scientist Profile

Early Career Scientist
University of California, Los Angeles
Biochemistry, Cell Biology