The research was funded through NIH grant GM048231 to JDS, and by NIH grants 7S10RR025107, 5R01GM086688 and 5R01RR023334 to JEB. Research in the Gonen laboratory was supported by the American Diabetes Association Career Development award 1-09-CD-05, NIH grants R01GM079233 and U54GM094598 and the Howard Hughes Medical Institute.
EMBO Molecular Medicine
Cataract -- Molecular aspects, Aquaporins, Calmodulin, Protein kinases
A decline in ocular lens transparency known as cataract afflicts 90% of individuals by the age 70. Chronic deterioration of lens tissue occurs as a pathophysiological consequence of defective water and nutrient circulation through channel and transporter proteins. A key component is the aquaporin-0 (AQP0) water channel whose permeability is tightly regulated in healthy lenses. Using a variety of cellular and biochemical approaches we have discovered that products of the A-kinase anchoring protein 2 gene (AKAP2/AKAP-KL) form a stable complex with AQP0 to sequester protein kinase A (PKA) with the channel. This permits PKA phosphorylation of serine 235 within a calmodulin (CaM)-binding domain of AQP0. The additional negative charge introduced by phosphoserine 235 perturbs electrostatic interactions between AQP0 and CaM to favour water influx through the channel. In isolated mouse lenses, displacement of PKA from the AKAP2–AQP0 channel complex promotes cortical cataracts as characterized by severe opacities and cellular damage. Thus, anchored PKA modulation of AQP0 is a homeostatic mechanism that must be physically intact to preserve lens transparency.
Gold, M. G., Reichow, S. L., O'neill, S. E., Weisbrod, C. R., Langeberg, L. K., Bruce, J. E., ... & Scott, J. D. (2012). AKAP2 anchors PKA with aquaporin‐0 to support ocular lens transparency. EMBO molecular medicine, 4(1), 15-26.