TRP Channels as Master Controllers of Lens Function

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To function normally, all cells must maintain ion homeostasis and regulate water content. The lens is unusual because it is made from a packed mass of fiber cells that are incapable of independently maintaining ion and water homeostasis. The fiber cells rely on ion transport mechanisms in a monolayer of epithelial cells at the lens surface. Na,K- ATPase and NKCC1 activity are particularly important. To monitor and control this arrangement, the lens has come to rely on exquisitely specialized remote control mechanisms that utilize TRPV4 and TRPV1 channels. A TRPV4 feedback loop senses swelling in the fiber mass and increases Na,K-ATPase activity to compensate. A TRPV1 feedback loop senses shrinkage in the fiber mass and increases NKCC1 activity to compensate. The feedback loops are important. They explain homeostatic regulation of lens ion transport as well as intracellular hydrostatic pressure, and they fit with the Mathias model of lens circulation. TRPV4 and TRPV1 appear to be master controllers of lens homeostasis. The specific aims are: (1) Test the hypothesis that the TRPV4/hemichannel/Na,K-ATPase response to swelling stretch involves a functional link between TRPV4 and the actin cytoskeleton; (2) Test the hypothesis that the TRPV1/ERK/NKCC1 response to shrinkage involves a functional link between TRPV1 and the tubulin cytoskeleton; (3) Explore reserve mechanisms of lens ion and water homeostasis. Aims 1 and 2 focus on unanswered mechanistic questions regarding TRPV4 and TRPV1 activation by opposing mechanical stimuli, TRPV4-dependent hemichannel opening, and the mechanism of NKCC1 activation. Aim 3 follows up pilot studies on reserve mechanisms that support slower homeostatic responses or serve as a fail-safe backup. The proposed studies are highly significant as regards human vision because preservation of lens transparency and refractive index gradient depends on ion and water homeostasis.