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Calcium Signaling in Specialized Glial Cells

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Calcium Signaling in Specialized Glial Cells GLIA 54:650–655 (2006) Calcium Signaling in Specialized Glial Cells MONICA R. METEA AND ERIC A. NEWMAN* Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota KEY WORDS signaling in Muller€ cells is believed to play an essential glia; calcium; Muller€ cell; Bergmann glia; radial glia role in these intercellular interactions. 1 ABSTRACT Spontaneous and Evoked Ca2 Signaling This article reviews calcium signaling in three specialized in Muller€ Cells types of glial cells: Muller€ cells of the retina, Bergmann glial cells of the cerebellum, and radial glial cells of the developing Muller€ cells of the mammalian retina generate transient cortex. Muller€ cells generate spontaneous and neuronal activ- increases in Ca21 in the absence of evoked neuronal activ- 21 € ity-evoked increases in Ca .NeurontoMuller cell signaling ity (Newman, 2005). They occur at a frequency of 4.6 tran- is mediated by neuronal release of ATP and activation of glial sients per cell per 1,000 s. The transients range from 2.5 to P2Y receptors. Muller€ cells, in turn, modulate neuronal excit- 6 s in duration and are similar to those observed in astro- ability and mediate vasomotor responses. Bergmann glial cells also generate spontaneous and activity-evoked Ca21 cytes in brain slices (Nett et al., 2002; Parri et al., 2001) increases. Neuron to Bergmann glia signaling is mediated by and in vivo (Hirase et al., 2004). neuronal release of nitric oxide, noradrenaline, and gluta- The retina offers an important advantage over brain 1 mate.InBergmannglia,Ca21 increases control the struc- slice preparations in studies of Ca2 signaling in that tural and functional interactions between these cells and Ca21 increases in Muller€ cells can be induced by a natural Purkinje cell synapses. In the ventricular zone of the devel- 1 stimulus, light. Neuronal activity, evoked by light flashes, oping cortex, radial glial cells generate spontaneous Ca2 21 € 21 increases the frequency of Ca transients in Muller cells increases that propagate as Ca waves through clusters of by 28% (Fig. 1) (Newman, 2005). This increase in Ca21 neighboring glial cells. These Ca21 increases control cell pro- transient frequency is greatly potentiated by adenosine, liferation and neurogenesis. VC 2006 Wiley-Liss, Inc. which is a degradation product of ATP. Adenosine poten- tiation of neuron-glia signaling is of clinical interest as INTRODUCTION adenosine levels increase in certain pathological states. Both endogenous and light-evoked Ca21 increases reflect 21 There is a dynamic, bidirectional signaling between Ca release from internal stores (Newman, 2005). The increases are blocked by cyclopiazonic acid, which depletes glial cells and neurons in the CNS. Much of what we 21 know of this interaction has been learned by monitoring Ca stores, and are abolished by heparin, which blocks changes in Ca21 within glial cells. Glial Ca21 signaling IP3 receptors (Newman and Zahs, 1997). € was first described in astrocytes. More recently, studies Signaling from neurons to Muller cells is mediated by of Ca21 signaling in specialized glial cells have added to release of ATP from neurons and activation of P2Y puri- nergic receptors (Newman, 2005), which evoke glial our knowledge of neuron-glia interactions. 21 21 This review summarizes research on Ca21 signaling in Ca increases. Light-evoked Ca increases are blocked three types of specialized CNS glia: Muller€ cells of the ret- by suramin, a purinergic antagonist, and by apyrase, ina, Bergmann glial cells of the cerebellum, and radial glia which hydrolyzes ATP, but not by antagonists to metabo- in the developing cortex. We will discuss Ca21 signaling tropic glutamate, GABA, or muscarinic receptors. Light- € 21 that is generated endogenously in these glial cells as well evoked Muller cell Ca increases are also blocked by as Ca21 signals evoked by neuronal activity. The physio- TTX, indicating that only those retinal neurons that 21 generate action potentials, amacrine and ganglion cells, logical consequences of such glial Ca increases will also € be addressed. are signaling to glial cells. Ganglion to Muller cell signal- ing was confirmed by antidromic activation of ganglion cells, which evokes Ca21 increases in Muller€ cells. MULLER€ CELLS € Muller cells are principal glial cells of the retina. They Grant sponsor: NIH; Grant number: EY004077; Grant Sponsor: NSF. span the entire thickness of the retina from the photore- *Correspondence to: Dr. Eric A. Newman, Department of Neuroscience, Univer- ceptors to the inner retinal surface. They are the only sity of Minnesota, 6-145 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA. E-mail: [email protected] type of macroglial cell present in most regions of the ret- Received 6 March 2006; Revised 22 March 2006; Accepted 5 April 2006 ina and function as specialized astrocytes. Muller€ cells DOI 10.1002/glia.20352 signal to retinal neurons and blood vessels, modulating 21 Published online 26 September 2006 in Wiley InterScience (www.interscience. neuronal activity and regulating arteriole diameter. Ca wiley.com). VC 2006 Wiley-Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America. CALCIUM SIGNALING IN SPECIALIZED GLIAL CELLS 651 Kettenmann, 2004). The insensitivity of Muller€ cells to glutamate may be a specialization to conditions in the ret- ina, where glutamate is released continuously from neu- rons. Mechanical stimulation of Muller€ cells also evokes Ca21 increases mediated by release from internal stores (Newman, 2001; Newman and Zahs, 1997). Stimulation of Muller€ cells and retinal astrocytes often evokes Ca21 increases that propagate from the activated cell to adjacent glial cells as intercellular waves (Newman, 2001; Newman and Zahs, 1997). Agonist ejection or me- chanical stimulation of Muller€ cells results in propagated intercellular Ca21 increases that travel outwards from the point of stimulation through neighboring glia (Newman, 2001). Muller€ cell to Muller€ cell signaling occurs via release of ATP from one cell and activation of purinergic receptors on adjacent cells. These waves are blocked by the purinergic antagonist, suramin. It is not known whether intercellular Ca21 waves occur in vivo. However, experimentally evoked waves result in the modulation of neuronal activity and in vasomotor responses (see below). Physiological Consequences of Ca21 Increases in Muller€ Cells Selective stimulation of Muller€ cells by agonist ejection evokes large Ca21 increases in these cells and subsequent hyperpolarization of adjacent ganglion cells. The ganglion cell hyperpolarization is mediated by ATP release from the Muller€ cells (Newman, 2003). Released ATP is rapidly con- verted to adenosine by ecto-ATPases and ecto-nucleoti- dases. Adenosine, in turn, activates A1 adenosine receptors on the ganglion cells, leading to the opening of K1 channels Fig. 1. Light-evoked Ca21 signaling in Muller€ cells. (A) Calcium flu- € and to cell hyperpolarization. It should be noted that orescence measured simultaneously in eight Muller cells. The retina 1 was exposed sequentially to a dim light, a bright flickering light, and a although glial stimulation results in glial Ca2 increases, it dim light (the light stimulus is shown at the bottom in A and B). Cal- has not been demonstrated directly that ATP release from cium transients are more likely to be generated during the flickering 21 light stimulus. (B) Mean Ca21 fluorescence averaged over 84 trials. The Muller€ cells is Ca dependent (Newman, 2003). flickering light evokes both a transient and a sustained increase in Muller€ cell stimulation may also lead to the release of Ca21. From (Newman, 2005). D-serine and to potentiation of NMDA receptor neuro- € € transmission in the retina. Muller cells contain D-serine, Studies on amphibian and mammalian Muller cells have an endogenous NMDA receptor co-agonist, and serine identified receptors linked to Ca21 increases. Responses to racemase, the synthetic enzyme for D-serine (Stevens ATP analogs indicate that P2Y ,P2Y,P2Y,P2Y,and 1 2 4 6 et al., 2003). Stimulation of astrocytes results in D-serine P2Y receptors can mediate Ca21 increases(Friesetal., 11 release (Schell et al., 1995), and a similar release of D- 2005; Reifel Saltzberg et al., 2003). Activation of A2B aden- serine may occur in Muller€ cells. osine receptors greatly potentiates ATP-evoked responses Muller€ cell stimulation by photolysis of caged-IP3 or (Newman, 2005), while activation of receptor tyrosine ki- caged-Ca21 results in vasomotor responses in neighboring nases causes a resensitization of P2Y receptors previously arterioles (Metea and Newman, 2006). Glial stimulation desensitized by agonist application (Weick et al., 2005). In € 21 can evoke either vasodilation or vasoconstriction. Both addition to ATP analogs, Muller cell Ca increases are responses are mediated by metabolites of arachidonic acid. evoked by dopamine, thrombin, and lysophosphatidic acid Vasodilation is mediated by production of EETs, while va- (Newman, 2003; Puro and Stuenkel, 1995). Calcium is 1 soconstriction by production of 20-HETE. It is not known released from internal stores by NAD (Esguerra and whether signaling from Muller€ cells to arterioles is Ca21- Miller, 2002), by ryanodine, and caffeine (Keirstead and dependent, although stimulation of Muller€ cells in this Miller, 1995) and following activation of metabotropic glu- study did evoke intracellular Ca21 increases. tamate receptors (Keirstead and Miller, 1997).
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