We hypothesize that the lens epithelium is able to sense and respond to changes in the entire cellular structure and adjust Na,K-ATPase activity accordingly. To function normally, maintain ion homeostasis, establish a membrane potential and regulate water content, all cells require active Na-K transport provided by Na,K-ATPase. The lens, however, is made up almost entirely of fiber cells that have little or no Na,K-ATPase activity. Lens ion and water homeostasis is made possible by a relatively few cells at the periphery of epithelium monolayer that somehow manage to match Na,K-ATPase activity to the needs of the entire cellular structure. Our studies in the last funding period indicate TRPV4 channels are able to trigger an increase of Na,K-ATPase activity, effectively making the Na,K-ATPase mechanosensitive. This enables the epithelium to detect and respond to swelling caused by ion imbalance in distant regions of the lens.
Aim 1 is a study of the sensor mechanism. We propose experiments to explain how mechanosensitive TRPV4 ion channels detect swelling and cause the epithelium to emit a purinergic agonist, ATP. The ATP causes a response that stimulates Na,K-ATPase.
Aim 2 is a study of the response mechanism. We propose experiments to explain how receptors, protein kinases and the regulatory protein Fxyd6 interact to increase Na,K- ATPase activity. Lens transparency depends on ion and water homeostasis. These lens studies will help explain how homeostasis is achieved. The significance to human well- being is the occurrence of cataract when homeostasis fails.
Lens transparency depends on correct maintenance of its ion and water content (homeostasis). Epithelial cells on the lens surface are able to sense and respond to swelling caused by ion imbalance in distant regions of the lens. The sensor is TRPV4, a mechanosensitive ion channel. We propose experiments to explain how TRPV4 ion channels detect swelling and cause the epithelium to emit a purinergic agonist, ATP. The ATP causes a response that stimulates Na,K- ATPase, and an ion pump. To study the response mechanism we propose experiments to explain how receptors, protein kinases and the regulatory protein Fxyd6 interact to increase Na,K- ATPase activity. The proposed studies will help explain how homeostasis is achieved. The significance to human well-being is the occurrence of cataract when homeostasis fails.
|Shahidullah, M; Mandal, A; Delamere, N A (2015) Damage to lens fiber cells causes TRPV4-dependent Src family kinase activation in the epithelium. Exp Eye Res 140:85-93|
|Mandal, Amritlal; Shahidullah, Mohammad; Delamere, Nicholas A (2015) Calcium entry via connexin hemichannels in lens epithelium. Exp Eye Res 132:52-8|
|Gao, Junyuan; Sun, Xiurong; White, Thomas W et al. (2015) Feedback Regulation of Intracellular Hydrostatic Pressure in Surface Cells of the Lens. Biophys J 109:1830-9|
|Beckel, Jonathan M; Argall, Arthur J; Lim, Jason C et al. (2014) Mechanosensitive release of adenosine 5'-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain. Glia 62:1486-501|
|Sanderson, Julie; Dartt, Darlene A; Trinkaus-Randall, Vickery et al. (2014) Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland. Exp Eye Res 127:270-9|
|Shahidullah, Mohammad; Mandal, Amritlal; Delamere, Nicholas A (2012) TRPV4 in porcine lens epithelium regulates hemichannel-mediated ATP release and Na-K-ATPase activity. Am J Physiol Cell Physiol 302:C1751-61|
|Shahidullah, M; Mandal, A; Beimgraben, C et al. (2012) Hyposmotic stress causes ATP release and stimulates Na,K-ATPase activity in porcine lens. J Cell Physiol 227:1428-37|
|Mandal, A; Shahidullah, M; Beimgraben, C et al. (2011) The effect of endothelin-1 on Src-family tyrosine kinases and Na,K-ATPase activity in porcine lens epithelium. J Cell Physiol 226:2555-61|
|Delamere, Nicholas A; Tamiya, Shigeo (2009) Lens ion transport: from basic concepts to regulation of Na,K-ATPase activity. Exp Eye Res 88:140-3|
|Khundmiri, Syed J; Amin, Vishal; Henson, Jeff et al. (2007) Ouabain stimulates protein kinase B (Akt) phosphorylation in opossum kidney proximal tubule cells through an ERK-dependent pathway. Am J Physiol Cell Physiol 293:C1171-80|
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