title: Mechanisms of ATP release, the enabling step in purinergic dynamics.
abstract: The only effective intervention to slow onset and progression of glaucomatous blindness is to lower intraocular pressure (IOP). Among other modulators, adenosine receptors (ARs) exert complex regulation of IOP. Agonists of A(3)ARs in the ciliary epithelium activate Cl(-) channels, favoring increased formation of aqueous humor and elevated IOP. In contrast, stimulating A(1)ARs in the trabecular outflow pathway enhances release of matrix metalloproteinases (MMPs) from trabecular meshwork (TM) cells, reducing resistance to outflow of aqueous humor to lower IOP. These opposing actions are thought to be initiated by cellular release of ATP and its ectoenzymatic conversion to adenosine. This view is now supported by our identification of six ectoATPases in trabecular meshwork (TM) cells and by our observation that external ATP enhances TM-cell secretion of MMPs through ectoenzymatic formation of adenosine. ATP release is enhanced by cell swelling and stretch. Also, enhanced ATP release and downstream MMP secretion is one mediator of the action of actin depolymerization to reduce outflow resistance. Inflow and outflow cells share pannexin-1 and connexin hemichannel pathways for ATP release. However, vesicular release and P2X(7) release pathways were functionally limited to inflow and outflow cells, respectively, suggesting that blocking exocytosis might selectively inhibit inflow, lowering IOP.
authors.affiliation: Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6085, USA.
authors.forename: Ang
authors.initials: A
authors.lastname: Li
authors.forename: Juni
authors.initials: J
authors.lastname: Banerjee
authors.forename: Chi Ting
authors.initials: CT
authors.lastname: Leung
authors.forename: Kim
authors.initials: K
authors.lastname: Peterson-Yantorno
authors.forename: W Daniel
authors.initials: WD
authors.lastname: Stamer
authors.forename: Mortimer M
authors.initials: MM
authors.lastname: Civan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001082:Aqueous Humor / Q000502:physiology; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism* / Q000502:physiology; D014129:Trabecular Meshwork / Q000378:metabolism / Q000502:physiology
chemical_list: D018047:Receptors, Purinergic P1; D000255:Adenosine Triphosphate; D020782:Matrix Metalloproteinases