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Differential frequency dependence of P2Y1- and P2Y2- mediated Ca 2+ signaling in astrocytes.

ABSTRACT: 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 Cbeta-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.

SUBMITTER: Fam SR

PROVIDER: S-EPMC6740798 | biostudies-literature | 2003 Jun

REPOSITORIES: biostudies-literature

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Differential frequency dependence of P2Y1- and P2Y2- mediated Ca 2+ signaling in astrocytes.

Fam Sami R SR Gallagher Conor J CJ Kalia Lorraine V LV Salter Michael W MW

The Journal of neuroscience : the official journal of the Society for Neuroscience 20030601 11

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 phosph ...[more]

PMID: 12805284

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Project description:The P2 purinergic receptor family implicated in many physiological processes, including neurotransmission, mechanical adaptation and inflammation, consists of ATP-gated non-specific cation channels P2XRs and G-protein coupled receptors P2YRs. Different cells, including bone forming osteoblasts, express multiple P2 receptors; however, how P2X and P2Y receptors interact in generating cellular responses to various doses of [ATP] remains poorly understood. Using primary bone marrow and compact bone derived osteoblasts and BMP2-expressing C2C12 osteoblastic cells, we demonstrated conserved features in the P2-mediated Ca2+ responses to ATP, including a transition of Ca2+ response signatures from transient at low [ATP] to oscillatory at moderate [ATP], and back to transient at high [ATP], and a non-monotonic changes in the response magnitudes which exhibited two troughs at 10-4 and 10-2 M [ATP]. We identified P2Y2 and P2X7 receptors as predominantly contributing to these responses and constructed a mathematical model of P2Y2R-induced inositol trisphosphate (IP3) mediated Ca2+ release coupled to a Markov model of P2X7R dynamics to study this system. Model predictions were validated using parental and CRISPR/Cas9-generated P2Y2 and P2Y7 knockouts in osteoblastic C2C12-BMP cells. Activation of P2Y2 by progressively increasing [ATP] induced a transition from transient to oscillatory to transient Ca2+ responses due to the biphasic nature of IP3Rs and the interaction of SERCA pumps with IP3Rs. At high [ATP], activation of P2X7R modulated the response magnitudes through an interplay between the biphasic nature of IP3Rs and the desensitization kinetics of P2X7Rs. Moreover, we found that P2Y2 activity may alter the kinetics of P2X7 towards favouring naïve state activation. Finally, we demonstrated the functional consequences of lacking P2Y2 or P2X7 in osteoblast mechanotransduction. This study thus provides important insights into the biophysical mechanisms underlying ATP-dependent Ca2+ response signatures, which are important in mediating bone mechanoadaptation.

Dataset Information

Differential frequency dependence of P2Y1- and P2Y2- mediated Ca 2+ signaling in astrocytes.

Publications

Differential frequency dependence of P2Y1- and P2Y2- mediated Ca 2+ signaling in astrocytes.

Similar Datasets

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