Proliferation of retinal glial (Müller) cells: Role of P2 receptors and potassium channels*

Müller glial cells of the vertebrate retina express purinergic P2 receptors; activation of these receptors causes an increase of the intracellular free calcium concentration and a subsequent activation of calcium-dependent potassium channels in the plasma membranes. The expression of these receptors varies among the animal species. Müller cells of all species investigated so far express metabotropic P2Y receptors while human Müller cells additionally express ionotropic P2X7 receptors. The expression level of functional purinergic receptors in Müller cells of the rabbit retina is dependent on the developmental stage. At the early postnatal stage, the vast majority of immature radial glial cells show calcium responses upon exposure to extracellular ATP whereas in the adult retina, only a minority of Müller cells shows such responses. However, in experimental proliferative retinal diseases, the ATP responsiveness increases significantly in correlation to alterations of the potassium conductances of the membrane. A similar disease-dependent up-regulation was found in human Müller cells, in respect to the expression of functional P2X7 receptors. Purinergic receptors are suggested to be implicated in the regulation of both retinal precursor cell proliferation in the developing retina and reactive Müller cell proliferation in the diseased adult retina. I. Purinergic receptors on Müller cells Since the first description on Müller cells of the tiger salamander retina by Keirstead and Miller [1], it becomes more and more obvious that adenosine 5'-triphosphate (ATP) is one of the major extracellular signaling molecules affecting Müller cell physiology. In the mature mammalian retina, ATP is released via extracellular calcium-dependent exocytosis, putatively from neuronal presynapses [2]. Another possible major source of extracellular ATP in the retina are glial cells. After different kinds of stimuli which induce calcium waves within the retinal glial cell network (particularly, after mechanical stress), ATP is released into the extracellular space [3]. The subsequent ATP-evoked autocrine and paracrine stimulation of purinergic receptors on glial cells is thought to be one main mechanism for mediating extraneuronal long-range calcium signaling in the retina [4]. These intercellular glial calcium waves alter the spontaneous and light-evoked activity of retinal ganglion cells [5]. Generally, extracellular ATP may activate two different families of purinergic receptors: G protein-coupled P2Y receptors and P2X receptors which represent ligandgated ion channels [6] Müller cells may express receptor subtypes of both the metabotropic and ionotropic receptor families; however, the expression patterns of functional P2