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The Journal of Neuroscience, June 1, 2003, 23(11):4437-4444

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Differential Frequency Dependence of P2Y₁- and P2Y₂- Mediated Ca ²⁺ Signaling in Astrocytes

Sami R. Fam,^1,2 Conor J. Gallagher,^1,3 Lorraine V. Kalia,^1,3 and Michael W. Salter^1,2,3

¹ Programme in Brain and Behaviour, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8, ² Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5G 1X8, and ³ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5G 1X8

ATP is a key extracellular messenger that mediates the propagation of Ca ²⁺ waves in astrocyte networks in various regions of the CNS. ATP-mediated Ca ²⁺ signals play critical roles in astrocyte proliferation and differentiation and in modulating neuronal activity. The actions of ATP on astrocytes are via two distinct subtypes of P2Y purinoceptors, P2Y₁ and P2Y₂ receptors (P2Y₁Rs and P2Y₂Rs), G-protein coupled receptors that stimulate mobilization of intracellular Ca ²⁺ ([Ca ²⁺]_i) via the phospholipase C-IP₃ pathway. We report here that P2Y₁R-mediated and P2Y₂R-mediated Ca ²⁺ responses differentially show two forms of activity-dependent negative feedback. First, Ca ²⁺ responses mediated by either receptor exhibit slow depression that is independent of stimulation frequency. Second, responses mediated by P2Y₁Rs, but not those mediated by P2Y₂Rs, show rapid oscillations after high-frequency stimulation. We demonstrate that the oscillations are mediated by recruiting negative feedback by protein kinase C, and we map the site responsible for the effect of protein kinase C to Thr³³⁹ in the C terminus of P2Y₁R. We propose that frequency-dependent changes in ATP-mediated Ca ²⁺ signaling pathways may modulate astrocyte function and astrocyte–neuron signaling in the CNS.

Key words: P2Y₁; P2Y₂; PKC; frequency; astrocytes; ATP; Ca ²⁺ signaling

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Received Oct. 18, 2002; revised Mar. 7, 2003; accepted Mar. 12, 2003.

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