title: Regulation of anterior chamber drainage by bicarbonate-sensitive soluble adenylyl cyclase in the ciliary body.
abstract: Glaucoma is a leading cause of blindness affecting as many as 2.2 million Americans. All current glaucoma treatment strategies aim to reduce intraocular pressure (IOP). IOP results from the resistance to drainage of aqueous humor (AH) produced by the ciliary body in a process requiring bicarbonate. Once secreted into the anterior chamber, AH drains from the eye via two pathways: uveoscleral and pressure-dependent or conventional outflow (C(t)). Modulation of "inflow" and "outflow" pathways is thought to occur via distinct, local mechanisms. Mice deficient in the bicarbonate channel bestrophin-2 (Best2), however, exhibit a lower IOP despite an increase in AH production. Best2 is expressed uniquely in nonpigmented ciliary epithelial (NPE) cells providing evidence for a bicarbonate-dependent communicative pathway linking inflow and outflow. Here, we show that bicarbonate-sensitive soluble adenylyl cyclase (sAC) is highly expressed in the ciliary body in NPE cells, but appears to be absent from drainage tissues. Pharmacologic inhibition of sAC in mice causes a significant increase in IOP due to a decrease in C(t) with no effect on inflow. In mice deficient in sAC IOP is elevated, and C(t) is decreased relative to wild-type mice. Pharmacologic inhibition of sAC did not alter IOP or C(t) in sAC-deficient mice. Based on these data we propose that the ciliary body can regulate C(t) and that sAC serves as a critical sensor of bicarbonate in the ciliary body regulating the secretion of substances into the AH that govern outflow facility independent of pressure.
authors: Department of Ophthalmology and Vision Science, University of Arizona, Tucson, Arizona 85719.
authors: Yong S
authors: YS
authors: Lee
authors: Department of Pharmacology, Weill Cornell College of Medicine, New York, New York 10065.
authors: Martin
authors: M
authors: Tresguerres
authors: Department of Pharmacology, Weill Cornell College of Medicine, New York, New York 10065.
authors: Kenneth
authors: K
authors: Hess
authors: Department of Ophthalmology and Vision Science, University of Arizona, Tucson, Arizona 85719; Department of Physiology, University of Arizona, Tucson, Arizona 85719.
authors: Lihua Y
authors: LY
authors: Marmorstein
authors: Department of Pharmacology, Weill Cornell College of Medicine, New York, New York 10065.
authors: Lonny R
authors: LR
authors: Levin
authors: Department of Pharmacology, Weill Cornell College of Medicine, New York, New York 10065.
authors: Jochen
authors: J
authors: Buck
authors: Department of Ophthalmology and Vision Science, University of Arizona, Tucson, Arizona 85719; College of Optical Sciences, University of Arizona, Tucson, Arizona 85719. Electronic address: amarmorstein@eyes.arizona.edu.
authors: Alan D
authors: AD
authors: Marmorstein
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001082:Aqueous Humor / Q000201:enzymology; D000075002:Bestrophins; D001639:Bicarbonates / Q000378:metabolism*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D002924:Ciliary Body / Q000201:enzymology*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005901:Glaucoma / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007429:Intraocular Pressure; D051379:Mice; D018345:Mice, Knockout; D013552:Swine
chemical_list: C465970:BEST2 protein, human; C497463:Best2 protein, mouse; D000075002:Bestrophins; D001639:Bicarbonates; D018118:Chloride Channels; D005136:Eye Proteins; D000262:Adenylyl Cyclases