Soluble adenylyl cyclase in the eye

Abstract

Adenylyl cyclases (AC) are a family of enzymes which convert ATP to cAMP an essential intermediate in many signal transduction pathways. Of the 10 AC genes in man, 9 fall into the category of transmembrane ACs (tmAC), which associate with G-protein coupled receptors (GPCRs) and are activated by forskolin. The 10th AC, termed soluble AC (sAC) is neither activated by forskolin nor does it interact with GPCRs. Rather, sAC can be found in many compartments within the cell and is activated by bicarbonate. As such, sAC is considered a major sensor of bicarbonate in many tissues. The pathways involving sAC vary in different tissues and organ systems, and are as diverse as facilitating sperm capacitation and regulating pressure in the eye. The role of sAC in the eye has only recently begun to receive significant attention. Here we summarize what is known about the roles of sAC in the eye.

Bicarbonate‐sensing soluble adenylyl cyclase is present in the cell cytoplasm and nucleus of multiple shark tissues

“…However, similar to sharks (this study), sAC is expressed throughout the mammalian cornea (Lee et al. ), where it regulates chloride permeability (Sun et al. ) and mediates protective HCO 3 − ‐dependent effects on cell health (Li et al.…”

Pharmacological modulation of the CO2/HCO3−/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase

“…CAI treatment of fluid-secreting non-pigmented epithelium ciliary body cells transiently increases cAMP production by bicarbonate-regulated sAC (Shahidullah et al, 2014). Because sAC regulates IOP (Gandhi et al, 2017; Lee et al, 2011; Lee & Marmorstein, 2014; Lee, Marmorstein, & Marmorstein, 2014), these data suggest CAI treatment lowers IOP via sAC; i.e., CAIs transiently increase HCO3− to stimulate sAC activity in ciliary body cells. These data also predict that a sAC activator may define a novel means of lowering IOP defining a new potential therapeutic strategy for treating glaucoma.…”

“…sAC has been shown to play a role in a number of physiological processes (Buffone, Wertheimer, Visconti, & Krapf, 2014; Chang, Beuers, & Oude Elferink, 2017; Desman, Waintraub, & Zippin, 2014; Ladilov & Appukuttan, 2014; Lee, Marmorstein, & Marmorstein, 2014; Levin & Buck, 2015; Muller, 2016; Schmid, Meili, & Salathe, 2014; Shim, Kim, & Ju, 2017; Stiles, Kapiloff, & Goldberg, 2014; Valsecchi, Konrad, & Manfredi, 2014). A number of sAC’s physiological roles have been identified genetically, via phenotypes observed in genetically engineered mice (Table 2).…”

Differential Intraocular Pressure Measurements by Tonometry and Direct Cannulation After Treatment with Soluble Adenylyl Cyclase Inhibitors

“…KH7 and LRE1, specific inhibitors of soluble adenylyl cyclase (sAC), have been proposed as therapeutic agents for ocular hypotony. [9][10][11] sAC is found in the ciliary body and is known to catalyze the formation of cAMP in response to increasing intracellular bicarbonate [HCO 3 -]. 12,13 KH7 has previously been shown to increase IOP in mice through direct cannulation.…”