In contrast, sAC does not have transmembrane domains and is localized in the cytoplasm compartments and within distinct organelles, such as nuclei and mitochondria ( 17, 22). The activity of tmACs is regulated by physical and functional interaction with G-protein coupled receptors (GPCRs) in the plasma membrane ( 19– 21). Each AC has various functional roles and distribution patterns in tissues ( 18, 19). To date, ten distinct AC genes (AC1-10) have been identified by molecular cloning techniques, and these genes encode nine mammalian transmembrane ACs (tmACs AC1-9), and a soluble AC (sAC AC10), respectively ( 15– 17). The activation of cAMP signaling causes opposite effects on cell survival in a cell-type-specific manner ( 8), because it exerts its effect through various effectors, such as cAMP-dependent protein kinase A (PKA) ( 9, 10), exchange protein directly activated by cAMP (Epac) ( 11, 12), and cyclic-nucleotide-gated ion channels ( 13, 14).Īmong the key regulators of the cAMP signaling pathway, ACs are enzymes that catalyze the synthesis of cAMP from adenosine 5′-triphosphate (ATP). Upon stimulation, cAMP synthesis and its degradation are tightly regulated by adenylyl cyclases (ACs) and cyclic nucleotide phosphodiesterases (PDEs), respectively ( 6). Its signaling pathway exists in all types of cells and contributes to numerous biological processes, such as cell growth, differentiation, death, gene expression, inflammatory cytokine secretion, and neurotransmission ( 5– 7) in the central nervous system (CNS). Regardless, the biological basis of glaucoma pathogenesis is not yet fully understood, and the factors contributing to its progression are currently not well characterized.Ĭyclic adenosine 3′,5′-monophosphate (cAMP) is the first discovered second messenger for signal transduction ( 4). Primary open-angle glaucoma (POAG), the most common form of open-angle glaucoma, is characterized by a slow and progressive degeneration of retinal ganglion cell (RGC) axons in the optic nerve head (ONH) and retinal nerve fiber layer, leading to an excavated appearance of the optic disc and visual impairment ( 1, 3). It has been estimated that glaucoma will affect more than 80 million individuals worldwide by 2020, with at least 6 to 8 million individuals becoming bilaterally blind ( 1, 2). Glaucoma is an optic neuropathy and the main cause of irreversible blindness worldwide ( 1– 3). Also, we will further focus on cAMP signaling in RGC growth and regeneration by soluble AC as well as ONH astrocytes by transmembrane ACs to understand its potential role in the pathogenesis of glaucoma neurodegeneration Keywords: Adenylyl cyclases, cAMP, Glaucoma, Optic nerve head astrocyte, Retinal ganglion cells In this review, we will discuss the functional role of cAMP in aqueous humor dynamics and IOP regulation, and review the current medications, which are related to the cAMP signaling pathway, for glaucoma treatment. Although recent studies revealed that cAMP generated by adenylyl cyclases (ACs) is important in regulating aqueous humor dynamics in ocular tissues, such as the ciliary body and trabecular meshwork, as well as cell death and growth in the retina and optic nerve, the functional role and significance of cAMP in glaucoma remain to be elucidated. The second messenger cyclic adenosine 3′,5′-monophosphate (cAMP) regulates numerous biological processes in the central nervous system including the retina and the optic nerve. However, lowering IOP itself is not always effective for preserving visual function in patients with primary open-angle glaucoma. Intraocular pressure (IOP) is the only modifiable risk factor, and reduction of IOP is the standard treatment for glaucoma. Despite its high prevalence, the biological basis of glaucoma pathogenesis still is not yet fully understood, and the factors contributing to its progression are currently not well characterized. Glaucoma is characterized by a slow and progressive degeneration of the optic nerve, including retinal ganglion cell (RGC) axons in the optic nerve head (ONH), leading to visual impairment.
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